Indolin-2-one derivatives

ABSTRACT

A compound represented by formula (I): wherein R 1  represents a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a trifluoromethyl group, a lower alkylthio group, an acyl group, a carboxyl group, a mercapto group or an amino group; R 2  represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an alkoxy group, an acyl group, an aryl group or a heterocyclic group; R 3  represents a lower alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group; R 4  represents a hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic group, --OR 5 , --SR 5  or --NR 6  R 7  (wherein R 5 , R 6 , and R 7  each represent a lower alkyl group, etc.); X and Y each represent --CH 2  --, --NH-- or --O--; and n represents an integer of from 0 to 4, and an intermediate for synthesis thereof are disclosed. The compound of the present invention exhibits selective antagonism against gastrin receptors without causing side effects attributed to CCK-A receptor antagonism and is useful for the treatment and prevention of peptic ulcers, gastritis, reflux esophagitis, and Zollinger-Ellison syndrome, and for the treatment of neoplasm originating in the gastrointestinal system.

This application is a divisional application of application Ser. No.08/963,547, filed on Nov. 3, 1997, now U.S. Pat. No. 5,932,511; which isa continuation application of application Ser. No. 08/448,579, filed onJun. 6, 1995, now abandoned; which is the §371 national application ofPCT International Application No. PCT/JP94/00235, filed on Feb. 17,1994. The entire contents of each of the above-identified applicationsare hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to an indolin-2-one derivative which exhibitsselective antagonism against gastrin receptors without causing sideeffects attributed to CCK-A receptor antagonism and is useful for thetreatment and prevention of diseases of digestive organs, such as pepticulcers, gastritis, reflux esophagitis, and Zollinger-Ellison syndrome,and for the treatment of tumours originating in the gastrointestinalsystem. The compounds also exhibit selective antagonism against CCK-Breceptors and are useful for the treatment of CCK-related disorders inthe appetite control system, enhancement and prolongation of analgesiathrough opiate or non-opiate, induction of anesthesia or analgesia, andthe treatment and prevention of symptoms of psychotic disordersincluding anxiety and panic disorder.

BACKGROUND OF THE INVENTION

Gastrin is a typical gastrointestinal hormone, like CCK, secretin, etc.It is known that gastrin accelerates secretion of gastric acid andpepsin and also accelerates growth of gastric mucous cells andespecially histamine secretory cells. While gastric acid secretion isstimulated by histamine, acetylcholine, and gastrin, gastrin is the mostpowerful of these internal substances. Currently known drugs forcontrolling gastric acid secretion include muscarinic receptorantagonists such as Pirenzepine, histamine H₂ receptor antagonists suchas Cimetidine, and H⁺ --K⁺ ATPase inhibitors such as Omeprazole.However, it has been reported that these drugs induce hypergastrinemiaduring maintained administration due to the potent inhibitory activityon gastric acid secretion, and the high gastrin level induces anincrease of histamine content in the gastric mucosa. The reports alsoreveal that discontinuation of administration of these drugs is followedby an increase of acid secretion, called rebound, and a high rate ofrelapses.

The study of gastrin has recently been progressed, and participation ofgastrin in various diseases has been elucidated. As a result, it hasbeen suggested that a selective antagonist to gastrin receptors would beuseful for the treatment and prevention of diseases induced by disordersof physiological functions related to gastrin, i.e., diseases ofdigestive organs, particularly peptic ulcers, gastritis, refluxesophagitis, and Zollinger-Ellison syndrome; prevention of a relapsefollowing treatment with an H₂ receptor antagonist or an H⁺ --K⁺ ATPaseinhibitor; or the treatment and prevention of tumours originating in thegastrointestinal system.

Recently, several gastrin receptor antagonists have been reported. Forexample, amino acid (glutamic acid) derivatives such as Proglumide andbenzodiazepin derivatives such as L-365,260 (Japanese Patent ApplicationLaid-Open No. 238069/88) are known. Proglumide exhibits very weakbinding activity to gastrin receptors. L-365,260, while having highbinding activity to gastrin receptors, do not exert powerful inhibitoryactivity on gastric acid secretion when administered in vivo.

On the other hand, CCK is widely distributed through thegastrointestinal system and the central nervous system. It is known thatCCK exhibits its activities at the peripheries chiefly via CCK-Areceptors accelerating pancreatic secretion, gastrointestinal motilityand contractions of the gall bladder, inhibition of gastric emptying,and acceleration of growth of some kinds of tumor cells. It is alsoknown that CCK participates in appetite control, analgesia throughopiate, and symptoms of psychotic disorders including anxiety and panicdisorder in the central nervous system via CCK-B receptors. Accordingly,drugs having a selective antagonistic action to CCK-B receptors areexpected to be useful for the treatment of CCK-related disorders in theappetite control system, enhancement and prolongation of analgesiathrough opiate or non-opiate, induction of anesthesia or analgesia, andthe treatment and prevention of symptoms of psychotic disordersincluding anxiety and panic disorders.

While amino acid (glutamic acid) derivatives such as Proglumide arereported as a CCK-B receptor antagonist, their binding activity to CCK-Breceptors is very weak.

An object of the present invention is to provide a compound whichselectively antagonizes to gastrin receptors without causing sideeffects attributed to the CCK-A receptor antagonism and inhibits gastricacid secretion in vivo and is useful for the treatment and prevention ofdiseases of digestive organs, such as peptic ulcers, gastritis, refluxesophagitis, and Zollinger-Ellison syndrome, and for the treatment oftumour originating in the gastrointestinal system and which alsoselectively antagonizes to CCK-B receptors without causing side effectsattributed to the CCK-A receptor antagonism and is useful for thetreatment of CCK-related disorders in the appetite control system,enhancement and prolongation of analgesia through opiate or non-opiate,induction of anesthesia or analgesia, and the treatment and preventionof symptoms of psychotic disorders including anxiety and panic disorder,and an intermediate useful for the synthesis of the compound.

DISCLOSURE OF THE INVENTION

We have conducted extensive investigations for the purpose of developinga selective gastrin receptor antagonist and a selective CCK-B receptorantagonist. As a result, we have found that the above purpose can beachieved by a compound represented by formula (I): ##STR1## wherein R₁represents a halogen atom, a lower alkyl group, a lower alkoxy group, ahydroxyl group, a nitro group, a trifluoromethyl group, a loweralkylthio group, an acyl group, a carboxyl group, a mercapto group, or asubstituted or unsubstituted amino group; R₂ represents a hydrogen atom,a substituted or unsubstituted lower alkyl group, a substituted orunsubstituted lower alkenyl group, a substituted or unsubstituted loweralkynyl group, a substituted or unsubstituted lower alkoxy group, asubstituted or unsubstituted acyl group, a substituted or unsubstitutedaryl group, or a substituted or unsubstituted heterocyclic group; R₃represents a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted heterocyclicgroup; R₄ represents a hydrogen atom, a substituted or unsubstitutedlower alkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heterocyclic group, --OR₅, --SR₅, or --NR₆R₇, wherein R₅, R₆, and R₇, which may be the same or different, eachrepresent a hydrogen atom, a substituted or unsubstituted lower alkylgroup, a substituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heterocyclicgroup, a lower alkoxy group, or a substituted or unsubstituted aminogroup; or R₆ and R₇ are taken together to form --(CH₂)_(m) -- or--(CH₂)_(l) NR₈ (CH₂)_(k) -- (wherein k, l, and m each represent aninteger of from 1 to 8; and R₈ represents a hydrogen atom or a loweralkyl group); X and Y, which may be the same or different, eachrepresent --CH₂ --, --NH-- or --O--; and n represents an integer of from0 to 4, or a salt thereof, thus having reached the present invention. Wehave also found that a compound represented by formula (II): ##STR2##wherein R₁, R₃, and n are as defined above; and R₉ represents a grouprepresented by formula (III): ##STR3## wherein R₁₀ and R₁₁ eachrepresent a substituted or unsubstituted lower alkyl group,

or a group represented by formula (IV): ##STR4## wherein Z represents asubstituted or unsubstituted lower alkylene group, and a compoundrepresented by formula (V): ##STR5## wherein R₁, R₉, and n are asdefined above, are useful intermediates for the synthesis of compoundrepresented by formula (I).

GENERAL DEFINITIONS OF TERMS USED

In the present invention, the term "lower alkyl group" denotes astraight-chain or branched alkyl group having 1 to 6 carbon atoms,including a methyl group, an ethyl group, a n-propyl group, an isopropylgroup, a n-butyl group, a sec-butyl group, a t-butyl group, a pentylgroup, and a hexyl group.

The term "lower alkenyl group" denotes a straight-chain or branchedalkenyl group having from 2 to 6 carbon atoms, including a vinyl group,an allyl group, a butenyl group, a pentenyl group, and a hexenyl group.

The term "lower alkynyl group" means a straight-chain or branchedalkynyl group having 2 to 6 carbon atoms, including an ethynyl group, apropynyl group, and a butynyl group.

The term "lower alkoxy group" denotes a straight-chain or branchedalkyloxy group having 1 to 6 carbon atoms, including a methyloxy group,an ethyloxy group, a n-propyloxy group, an isopropyloxy group, an-butyloxy group, a sec-butyloxy group, a t-butyloxy group, a pentyloxygroup, and a hexyloxy group.

The term "acyl group" indicates a carbonyl group attaching a hydrogenatom, a substituted or unsubstituted alkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted alkoxy group, asubstituted or unsubstituted amino group, etc., including analkylcarbonyl group, such as an acetyl group, a propionyl group, apivaloyl group, and a cyclohexanecarbonyl group; and an arylcarbonylgroup, such as a benzoyl group, a naphthoyl group and a toluoyl group.

The term "aryl group" means an aromatic hydrocarbon with one hydrogenatom removed therefrom, such as a phenyl group, a tolyl group, a xylylgroup, a biphenyl group, a naphthyl group, an anthryl group, or aphenanthryl group.

The term "alkylene group" denotes a straight-chain or branched alkylenegroup having 1 to 6 carbon atoms, including a methylene group, anethylene group, a propylene group, a butylene group, a pentylene group,and a hexylene group.

The term "cycloalkyl group" denotes a cyclic saturated hydrocarbon grouphaving 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group.The substituted cycloalkyl group includes a menthyl group and anadamantyl group.

The term "aralkyl group" denotes a lower alkyl group substituted with anaryl group, such as a benzyl group, a diphenylmethyl group, a tritylgroup, a phenethyl group or a naphthylmethyl group, with a benzyl groupor phenethyl group being preferred.

The term "heterocyclic group" means an aromatic heterocyclic grouphaving at least one hetero atom, such as a pyridyl group, a furyl group,a thienyl group, an imidazolyl group, a pyrazinyl group or a pyrimidylgroup.

The "substituent" includes a halogen atom, a lower alkyl group., acycloalkyl group, an aryl group, a hydroxyl group, an alkoxy group, anaryloxy group, an alkylthio group, a heterocyclic group, a formyl group(which may be protected with an acetal, etc.), an alkylcarbonyl group,an arylcarbonyl group, a carboxyl group, an alkoxycarbonyl group, asubstituted or unsubstituted amino group, an imino group, a thioacetalgroup, a nitro group, a nitrile group, and a trifluoromethyl group.

R₁ is preferably a lower alkyl group or nil (n=0), still preferably nil(n=0).

R₂ is preferably an alkoxy-substituted lower alkyl group, stillpreferably a lower alkyl group having two alkoxy groups or an--O--Z--O-- group (wherein Z represents a substituted or unsubstitutedlower alkylene group) on one carbon atom thereof. A 2,2-diethoxyethylgroup is particularly preferred.

R₃ is preferably a substituted or unsubstituted aryl group, stillpreferably a phenyl group substituted with a lower alkyl group or alower alkoxy group. A phenyl group substituted with a methyl group or amethoxy group is particularly preferred.

R₄ is preferably --NR₆ R₇ in which one of R₆ and R₇ is a hydrogen atomwith the other being a substituted or unsubstituted aryl group or asubstituted or unsubstituted heterocyclic group, still preferably --NR₆R₇ in which one of R₆ and R₇ is a hydrogen atom with the other being aphenyl group substituted with a lower alkyl group, a lower alkoxy groupor a substituted or unsubstituted amino group, particularly a phenylgroup substituted with a methyl group or an N,N-dimethylamino group.

X is preferably --NH--.

Y is preferably --CH₂ --.

Of optically active compounds of formula (I) or salts thereof preferredare (+)-compounds.

The compounds of the present invention are novel compounds which havenot been reported in any literature and can be synthesized, for example,as follows. ##STR6## wherein R₁, R₃, and n are as defined above; R₁₂represents a lower alkyl group; R'₂ represents a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted loweralkenyl group, a substituted or unsubstituted lower alkynyl group, asubstituted or unsubstituted aryl group, or a substituted orunsubstituted heterocyclic group; and X represents a halogen atom or atrifluoromethanesulfonyloxy group. ##STR7## wherein R₁, R'₂, R₃, X, andn are as defined above; and R₁₃ represents a lower alkyl group. ##STR8##wherein R₁, R'₂, R₃, R₁₃, and n are as defined above; R' represents alower alkyl group; and R₁₄ represents a substituted or unsubstitutedlower alkyl group, a substituted or unsubstituted cycloalkyl group, asubstituted or unsubstituted aryl group, or a substituted orunsubstituted heterocyclic group. ##STR9## wherein R₁, R'₂, R₃, R₁₃, andn are as defined above; and R₁₅ and R₁₆, which may be the same ordifferent, each represent a hydrogen atom, a substituted orunsubstituted lower alkyl group, a substituted or unsubstitutedcycloalkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heterocyclic group, a lower alkoxy group,or a substituted or unsubstituted amino group; or R₁₅ and R₁₆ are takentogether to form --(CH₂)_(m) -- or --(CH₂)_(l) NR₈ (CH₂)_(k) --, whereink, l, and m each represent an integer of from 1 to 8; and R₈ representsa hydrogen atom or a lower alkyl group. ##STR10## wherein R₁, R'₂, R₃,R₁₃, R₁₅, R₁₆, and n are as defined above; and R_(a) preferablyrepresents a substituted or unsubstituted lower alkyl group, stillpreferably a substituted or unsubstituted methyl group, most preferablya methyl group or a benzyl group. ##STR11## wherein R₁, R₃, R₁₅, R₁₆,and n are as defined above; R₂₆ represents a lower alkyl group; R₁₇represents a lower alkyl group or a lower hydroxyalkyl group; R₁₈ andR₁₉ each represent a lower alkyl group, or they are taken together toform an alkylene group; R₂₀ represents a lower alkyl group or a lowermercaptoalkyl group; R₂₂ and R₂₃ each represent a lower alkyl group, orthey are taken together to form an alkylene group; and R₂₄ and R₂₅ eachrepresent a lower alkyl group, or they are taken together to form analkylene group. ##STR12## wherein R₁, R'₂, R₃, R₁₅, R₁₆, and n are asdefined above; R" represents a lower alkyl group, a primary amino group,a secondary amino group or an alkoxy group; and R₂₁ * represents anoptically active group. ##STR13## wherein R₁, R'₁ and n are as definedabove.

Diurea derivative (5) can be prepared by substitution reaction betweenthe acetal moiety of acetal intermediate (4) and an urea derivative asshown in Reaction Route 1. Intermediate (4) can be prepared by tworeactions, i.e., alkylation and acetal formation, whichever may precede,as shown in Reaction Route 1.

The isatin derivative which can be used as a starting material in thisprocess is a known compound and is commercially available or can easilybe synthesized in a conventional manner. Various urea derivatives arealso commercially available or can easily be synthesized in aconventional manner (J. Heterocyclic Chem., Vol. 19, p. 1453 (1982)).

The preparation of diurea derivative (5) can preferably be carried outas follows. Isatin derivative (1) is dissolved or suspended in an inertsolvent, such as dry N,N-dimethylformamide, dry dimethyl sulfoxide ordry tetrahydrofuran, and a requisite amount of a base, such as a metalhydride or a metal alkoxide, preferably sodium hydride or potassiumt-butoxide, is added thereto at a temperature in the range fromice-cooling to room temperature. After stirring the mixture for a whileat a temperature in the range from ice-cooling to room temperature, anequimolar amount or a slight excess, with respect to isatin derivative(1), of a halide is added thereto, followed by stirring for 1 to 15hours at room temperature or under heating. After completion of thereaction, the solvent is removed by evaporation under reduced pressure.Water is added to the residue, and the mixture is extracted with anappropriate solvent, such as chloroform or ethyl acetate, dried, andconcentrated under reduced pressure. The resulting crude product ispurified by a proper method to obtain N-substituted isatin (3).

Then, N-substituted isatin (3) and an adequate amount of an appropriatetrialkyl orthoformate are dissolved or suspended in an appropriatealcohol, and an adequate amount of an acid catalyst, for example,p-toluenesulfonic acid monohydrate, camphorsulfonic acid or sulfuricacid, is added thereto, followed by heating for 4 to 48 hours withstirring. The reaction mixture is concentrated under reduced pressure,and to the residue is added a base, for example, saturated aqueoussodium hydrogencarbonate, followed by extraction with an appropriatesolvent, such as chloroform or ethyl acetate. The extract is dried andconcentrated under reduced pressure. The resulting crude product ispurified by an appropriate method to obtain acetal intermediate (4).

Alternatively, acetal intermediate (4) can be obtained by conducting theabove-mentioned two reactions in reverse order, i.e., via intermediate(2) shown in Reaction Route 1. This process is preferred in case wherethe reaction for synthesizing N-substituted isatin (3) requires heating.

An excess, with reference to acetal intermediate (4), preferably 2 to 3mol, per mol of acetal intermediate (4), of a Lewis acid, such asanhydrous aluminum chloride, boron trifluoride ethyl etherate, titaniumtetrachloride, tin tetrachloride, magnesium bromide ethyl etherate, orzinc bromide, preferably anhydrous aluminum chloride, is dissolved in aninert solvent, such as dry tetrahydrofuran, dichloromethane, toluene, ordry dioxane, preferably dry tetrahydrofuran. To the solution are addedsuccessively a solution of acetal intermediate (4) in drytetrahydrofuran, etc. and an urea derivative in excess, preferably in anamount of 2 mol per mol of acetal intermediate (4) at a temperature inthe range from ice-cooling to room temperature, followed by heating for1 to 8 hours with stirring. After completion of the reaction, anappropriate organic solvent, such as ethyl acetate, is added to thereaction mixture, and the mixture is washed with water, dried, andconcentrated under reduced pressure. The residue is purified by a propermethod to obtain diurea derivative (5).

Diamide derivative (10) can be prepared by dialkylation of the3-position of commercially available 2-oxindole (6), followed byalkylation of the 1-position, followed by conversion of ester to amideas illustrated in Reaction Route 2.

The preparation of diamide derivative (10) can preferably be carried outas follows. 2-Oxindole (6) is dissolved in an inert solvent, such as drydimethyl sulfoxide, dry N,N-dimethylformamide or dry tetrahydrofuran,preferably dry dimethyl sulfoxide, and a solution of an equimolar amountof a base, such as a metal hydride or a metal alkoxide, preferablysodium hydride or potassium t-butoxide, in dry dimethyl sulfoxide isadded thereto at a temperature in the range from ice-cooling to roomtemperature, followed by stirring at a temperature in the range fromice-cooling to room temperature for several minutes. An equimolar amountof an appropriate bromoacetic ester with reference to (6) is then addedthereto, followed by stirring at room temperature for several tens ofminutes. To the reaction mixture are further added an equimolar amountof the same base as used above and an equimolar amount of the samebromoacetic ester as used above at the same temperature, followed bystirring at room temperature for several tens of minutes. Aftercompletion of the reaction, water is added to the residue, and themixture is extracted with an appropriate solvent, such as diethyl ether.The extract is dried and concentrated under reduced pressure. Since theresulting crude product contains a 1-substituted derivative, it ispurified by a proper method, such as silica gel column chromatography,to give both 3,3-bis(alkoxycarbonylmethyl)indolin-2-one (7) and1,3,3-tris(alkoxycarbonylmethyl)indolin-2-one.

3,3-Bis(alkoxycarbonylmethyl)indolin-2-one (7) is dissolved or suspendedin an inert solvent, such as dry N,N-dimethylformamide, dry dimethylsulfoxide or dry tetrahydrofuran, and a requisite amount of a base, suchas a metal hydride or a metal alkoxide, preferably sodium hydride orpotassium t-butoxide, is added thereto at a temperature in the rangefrom ice-cooling to room temperature, followed by stirring for severalminutes at a temperature in the range from ice-cooling to roomtemperature. An equimolar amount or a slight excess, with respect to(7), of an appropriate halide is added thereto, followed by stirring for1 to 15 hours at room temperature or under heating. After completion ofthe reaction, the solvent is removed by evaporation under reducedpressure. Water is added to the residue, and the mixture is extractedwith an appropriate solvent, such as chloroform or ethyl acetate, dried,and concentrated under reduced pressure. The resulting crude product maybe either purified by a proper method to obtain 1-substituted3,3-bis(alkoxycarbonylmethyl)indolin-2-one (8) or be used in thesubsequent reaction without further purification.

1-Substituted 3,3-bis(alkoxycarbonylmethyl)indolin-2-one (8) isdissolved in a solvent uniformly miscible with water, such as ethanol ormethanol, and an aqueous solution of a moderately excess base, such aspotassium hydroxide, sodium hydroxide or potassium carbonate, is addedthereto at room temperature, followed by stirring for 1 to 24 hours atroom temperature or under heating. After completion of the reaction, thereaction mixture is concentrated under reduced pressure. The concentrateis dissolved in water and washed with an appropriate organic solvent,such as chloroform. The aqueous layer is acidified with an acid, e.g.,2N hydrochloric acid and then extracted with an appropriate organicsolvent, such as ethyl acetate, to obtain 1-substituted3,3-bis(hydroxycarbonylmethyl)indolin-2-one (9). The crude product asobtained may be used in the subsequent reaction either withoutpurification or after being purified by an appropriate method.

1-Substituted 3,3-bis(hydroxycarbonylmethyl)indolin-2-one (9) isconverted to an amide compound in a conventional manner to obtaindiamide compound (10). For example, 1-substituted3,3-bis(hydroxycarbonylmethyl)indolin-2-one (9) is dissolved in an inertsolvent, such as dry N,N-dimethylformamide or dichloromethane, and 2 to4 moles, per mol of (9), of dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is addedthereto as a condensing agent. Subsequently, 0 to 4 mol of1-hydroxybenzotriazole or 4-dimethylaminopyridine as an activating agentand 2 to 4 mol of an amine, each per mol of (9) are preferably addedthereto at room temperature. The mixture is stirred at room temperaturefor 6 to 24 hours. To the reaction mixture, either as obtained or afterconcentration under reduced pressure, is added dilute hydrochloric acid.The product is extracted with an appropriate organic solvent, and theorganic layer is washed with an appropriate base, such as saturatedaqueous sodium hydrogencarbonate, dried, and concentrated. Theconcentrate is purified by an appropriate method to obtain diamidecompound (10).

As shown in Reaction Route 3, monocarbamate (13) can be prepared byAldol reaction of N-substituted isatin derivative (3) as a startingmaterial, conversion of the reaction product to an amide compound, andreaction of the resulting tertiary alcohol (12) with an isocyanate usinga catalyst.

The preparation of monocarbamate derivative (13) can preferably becarried out as follows. A lithium enolate of an acetic ester is preparedby mixing a lithium salt of a secondary amine, such as lithiumdiisopropylamide or lithium hexamethyldisilazide, with an acetic esterat an equimolar ratio in a solvent which gives no adverse influence tothe reaction, such as dry tetrahydrofuran, dry diethyl ether or drydioxane, preferably dry tetrahydrofuran, by stirring under a nitrogenatmosphere at a low temperature for several minutes. To the resultingreaction solution is added 0.5 mol of N-substituted isatin (3) per molof the lithium enolate at a low temperature, followed by stirring at alow temperature for several tens of minutes, and the reaction mixture ispoured into water to quench the reaction. The reaction product isextracted with an appropriate organic solvent, and the extract is driedand concentrated to obtain ester intermediate (11). This crude product(11) may be used in the subsequent reaction either without purificationor after purification by a proper method.

An amine is dissolved in a solvent giving no adverse influence to thereaction, such as dry tetrahydrofuran, dry diethyl ether or dry dioxane,preferably dry tetrahydrofuran, and an equimolar amount of an alkyllithium, preferably n-butyl lithium, is added to the solution under anitrogen atmosphere at a low temperature, followed by stirring at a lowtemperature for several minutes. To the resulting solution is added 0.5mol of ester intermediate (11) per mol of the amine, and the mixture isstirred at a low temperature for several tens of minutes. The reactionmixture is poured into water to quench the reaction, and the product isextracted with an appropriate organic solvent. The extract is dried andconcentrated, and the concentrate is purified by a proper method toobtain amide intermediate (12).

Amide intermediate (12) and excess isocyanate compound are dissolved inan inert solvent, such as dry tetrahydrofuran, dichloromethane,acetonitrile or toluene, preferably dry tetrahydrofuran, and a smallproportion, with reference to (12), of an acid or a base, such as atitanium tetraalkoxide, a boron trifluoride ethyl etherate, dibutyltindiacetate or diisopropylethylamine, preferably dibutyltin diacetate, isadded to the solution, followed by stirring for 10 to 24 hours at roomtemperature or under heating. The reaction mixture is washed with water,extracted with an appropriate solvent, dried, and concentrated. Theconcentrate is purified by a proper method to obtain monocarbamatecompound (13).

Monourea compound (19) can be prepared through either of the processesillustrated in Reaction Routes 4 and 5.

Some ureido intermediates (15) shown in Reaction Route 4 are knowncompounds and can be synthesized by starting with isatin derivative (1)in accordance with the process described in patents (Japanese PatentPublication Nos. 6710/92 and 6711/92). An acetic ester is bonded to thethus prepared ureido intermediate (15), and the resulting ester ishydrolyzed to give carboxylic acid (17). The 1-position of (17) isselectively alkylated to give compound (18), which is then converted tomonourea compound (19) by amidation. The alkylation and the subsequentamidation of carboxylic acid (17) may be carried out in one step.

Ureido intermediate (23) in Reaction Route 5 can be synthesized bystarting with N-substituted isatin (3) in accordance with the processdescribed in patents (Japanese Patent Publication Nos. 6710/92 and6711/92). Alternatively, it may be prepared by converting isatinderivative (1) to alkyloxime or aralkyloxime (20), for example,methyloxime or benzyloxime, alkylating the 1-position, hydrogenation ofoxime, and then leading the product to urea. N-Substituted isatin (3)can also be synthesized by alkylating the 1-position of starting indole(32) to obtain 1-substituted indole (33), followed by oxidizing theindole ring with, for example, sodium hypochlorite to give (34), whichis then hydrolyzed as shown in Reaction Route 8. Where a bulky group,such as a secondary alkyl group, a 2,2-dialkoxyethyl group or a2,2-dialkylethyl group, is to be introduced to the 1-position, thereaction route by way of alkyloxime or aralkyloxime (20) or the routeincluding oxidation of 1-substituted indole (33) are preferred. Anacetic ester is bonded to the thus prepared ureido intermediate (23),and the resulting ester is hydrolyzed to give carboxylic acid (18),which is then converted to monourea compound (19) by amidation.Alternatively, an acetamide derivative can directly be added to (23) toprepare (19). Most of bromoacetamide derivatives (25) which can be usedin this reaction are known compounds and can easily be synthesized bymixing bromoacetyl bromide and an amine in the presence of a base.

The preparation of monourea compound (19) through Reaction Route 4 canpreferably be carried out as follows. Isatin derivative (1) is dissolvedin an inert solvent, such as ethanol or methanol, and an equimolar orexcessive molar amount, with reference to (1), of a hydroxylaminehydrochloride or a hydroxylamine sulfate, and the same quantity of abase, such as a sodium acetate aqueous solution, are added thereto,followed by stirring for 1 to 10 hours at room temperature or underice-cooling. The reaction mixture is concentrated, and the concentrateis purified by a proper method to give oxime derivative (14). Oximederivative (14) is stirred in an inert solvent, such as ethanol,methanol or acetic acid, in the presence of an appropriate catalyst,such as palladium-on-carbon, rhodium-on-carbon, platinum oxide, or Raneynickel, under a hydrogen atmosphere of 1 to 6 atm at room temperature.After removal of the catalyst by filtration, the filtrate isconcentrated to give an amine intermediate. Since this compound issusceptible to air oxidation, it is preferably subjected to thesubsequent reaction without further purification. The unpurified productis dissolved in an inert solvent, such as dichloromethane, chloroform,N,N-dimethylformamide, or acetonitrile, and an equimolar or slightlyexcessive amount, with reference to the amine, of an isocyanate is addedthereto at a temperature in the range from ice-cooling to roomtemperature, followed by stirring at a temperature in the range fromice-cooling to room temperature for 1 to 10 hours. The reaction productis purified by a proper method to give ureido intermediate (15).

Ureido intermediate (15) is dissolved in an inert solvent, such as dryN,N-dimethylformamide, dry dimethyl sulfoxide or dry tetrahydrofuran,preferably dry dimethyl sulfoxide, and a solution of an equimolaramount, with reference to ureido intermediate (15), of a base, such as ametal hydride or a metal alkoxide, preferably sodium hydride orpotassium t-butoxide, in dry dimethyl sulfoxide is added thereto at atemperature in the range from ice-cooling to room temperature, followedby stirring at a temperature in the range from ice-cooling to roomtemperature for 10 to 30 minutes. Then, a bromoacetic ester is addedthereto in an equimolar amount with reference to ureido intermediate(15), and the mixture is stirred at room temperature for several tens ofminutes. After completion of the reaction, water is added to thereaction mixture, and the mixture is extracted with an appropriatesolvent, such as diethyl ether. The extract is dried and concentratedunder reduced pressure, and the residue is purified by a proper methodto obtain ester compound (16).

Ester compound (16) is stirred in a solvent uniformly miscible withwater, such as ethanol or methanol, together with an aqueous solution ofa moderate excess of a base, such as potassium hydroxide, sodiumhydroxide or potassium carbonate, at room temperature for 1 to 24 hours.After completion of the reaction, the reaction mixture is concentratedunder reduced pressure. The concentrate is dissolved in water and washedwith an appropriate organic solvent, such as chloroform. The aqueouslayer is acidified with 2N hydrochloric acid and then extracted with anappropriate organic solvent, such as ethyl acetate, to obtain carboxylicacid (17). The resulting crude product may be used in the subsequentreaction either as it is or after being purified by a proper method.

Carboxylic acid (17) is dissolved in a solvent giving no adverseinfluence to the reaction, such as dry dimethyl sulfoxide or drytetrahydrofuran, preferably dry dimethyl sulfoxide, and a solution of 2mol, per mol of carboxylic acid (17), of a base, such as a metal hydrideor a metal alkoxide, preferably sodium hydride or potassium t-butoxide,in dry dimethyl sulfoxide is added thereto at room temperature, followedby stirring at room temperature for 10 to 30 minutes. A halide is addedthereto in an equimolar amount with carboxylic acid (17), followed bystirring at room temperature for several tens of minutes. Aftercompletion of the reaction, water is added to the reaction mixture, andthe mixture is extracted with an appropriate solvent, such as diethylether. The extract is dried and concentrated under reduced pressure toobtain 1-alkyl compound (18). The resulting crude product may be used inthe subsequent reaction either as it is or after being purified by aproper method.

1-Alkyl compound (18) is dissolved in an inert solvent, such as dryN,N-dimethylformamide or dichloromethane, and 1 to 4 mol, per mol of1-alkyl compound (18), of a condensing agent, such asdicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, is added tothe solution. To the solution are further added successively 0 to 4 molof 1-hydroxybenzotriazole or 4-dimethylaminopyridine as an activatingagent and 1 to 4 mol of an amine, each per mol of 1-alkyl compound (18)at room temperature. The mixture is stirred at room temperature for 1 to24 hours.

Alternatively, 1-alkyl compound (18) is dissolved in an inert solvent,such as chloroform or dichloromethane, and an equimolar amount or aslight excess, with reference to 1-alkyl compound (18), of a base, suchas 4-dimethylaminopyridine, triethylamine, pyridine or a mixturethereof, and an equimolar amount of a halogenating agent, preferablythionyl chloride, are added thereto at 0° C. to room temperature. Afterstirring the mixture for 30 minutes to 2 hours, an equimolar amount or aslight excess, with reference to 1-alkyl compound (18), of a base, suchas 4-dimethylaminopyridine, triethylamine, pyridine or a mixturethereof, and an equimolar amount or a slight excess of an amine areadded thereto, followed by stirring at room temperature or underice-cooling for 30 minutes to 4 hours.

Dilute hydrochloric acid is added to the reaction mixture either asobtained or after being concentrated under reduced pressure, and themixture is extracted with an appropriate organic solvent. The organiclayer is washed with an appropriate base, such as saturated aqueoussodium hydrogencarbonate, dried, and concentrated. The residue ispurified by an appropriate method to give monourea compound (19).

Monourea compound (19) can also be prepared from carboxylic acid (17)without isolating (18). Carboxylic acid (17) is dissolved in a solventgiving no adverse influence to the reaction, such as dryN,N-dimethylformamide, dry dimethyl sulfoxide or dry tetrahydrofuran,preferably dry dimethyl sulfoxide. A solution of 2 mol, per mol ofcarboxylic acid (17), of a base, such as a metal hydride or a metalalkoxide, preferably sodium hydride or potassium t-butoxide, in drydimethyl sulfoxide is added to the solution at room temperature,followed by stirring at room temperature for 10 to 30 minutes. To themixture is further added a halide in an equimolar amount with carboxylicacid (17), followed by stirring at room temperature for several tens ofminutes. After completion of the reaction, 1 to 3 mol, per mol ofcarboxylic acid (17), of a condensing agent, such asdicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added tothe reaction mixture. Subsequently, 0 to 3 mol, per mol of 1-alkylcompound (18), of 1-hydroxybenzotriazole or 4-dimethylaminopyridine ispreferably added thereto as an activating agent, and then 1 to 3 mol,per mol of 1-alkyl compound (18), of an amine is further added thereto,followed by stirring at room temperature for 6 to 24 hours. Water isadded to the reaction mixture, and the mixture is extracted with anappropriate solvent, such as diethyl ether. The extract is dried,concentrated under reduced pressure, and purified by an appropriatemethod to give monourea compound (19).

The preparation of monourea compound (19) through Reaction Route 5 canpreferably be carried out as follows. First of all, ureido intermediate(23) with its 1-position alkylated is prepared by starting withN-substituted isatin (3), which is synthesized by the process shown inReaction Route 8 or by alkylation of isatin derivative (1), in the samemanner as in the preparation of ureido intermediate (15) shown inReaction Route 4. Alternatively, ureido intermediate (23) may beprepared as follows. Isatin derivative (1) is dissolved or suspended inan inert solvent, such as ethanol or methanol, and to the solution orsuspension are added an equimolar or excess molar amount, with referenceto (1), of an O-alkylhydroxylamine or an O-aralkylhydroxylamine, such asO-methyl or benzylhydroxylamine hydrochloride, and an aqueous solutionof excess base, such as sodium acetate, and the mixture is stirred atroom temperature for 1 to 10 hours. The reaction mixture is concentratedand purified by a proper method to obtain alkyloxime (e.g., methyloxime)or aralkyloxime (e.g., benzyloxime) derivative (20). Then, an equimolaramount or a slight excess, with reference to (20), of a base, such assodium hydride or potassium t-butoxide, is dissolved or suspended in aninert solvent, such as dry N,N-dimethylformamide, dry dimethyl sulfoxideor dry tetrahydrofuran. Alkyloxime derivative or aralkyloxime derivative(20) is added to the solution or suspension at room temperature or underice-cooling. After stirring at the same temperature for 30 minutes to 1hour, an equimolar amount or a slight excess, with reference to (20), ofa halide is added thereto, followed by further stirring at roomtemperature or under heating for 1 to 15 hours. After completion of thereaction, the solvent was evaporated under reduced pressure, water isadded to the residue, and the mixture is extracted with an appropriatesolvent. The extract is dried and concentrated under reduced pressure.The resulting crude product is purified by a proper method to obtainN-substituted compound (21), which is hydrogenated and reacted withisocyanate in the same manner as for the preparation of ureidointermediate (15) shown in Reaction Route 4 to thereby obtain ureidointermediate (23) with the 1-position alkylated.

The thus obtained ureido intermediate (23) is subjected to acetic esteraddition reaction and ester hydrolysis reaction as shown in ReactionRoute 5 in the same manner as in the preparation of carboxylic acid (17)shown in Reaction Route 4 to give intermediate (18) common to bothreaction routes, which is converted to monourea compound (19) in thesame manner as in Reaction Route 4.

Alternatively, monourea compound (18) can be prepared from ureidointermediate (23) in one step as described below. Ureido intermediate(23) is dissolved in an inert solvent, such as dryN,N-dimethylformamide, dry dimethyl sulfoxide or dry tetrahydrofuran,preferably dry dimethyl sulfoxide. To the solution is added a solutionof an equimolar amount, with reference to ureido intermediate (23), of abase, such as a metal hydride or a metal alkoxide, preferably sodiumhydride or potassium t-butoxide, in dried dimethyl sulfoxide at atemperature in the range from ice-cooling to room temperature, followedby stirring at a temperature in the range from ice-cooling to roomtemperature for 10 to 30 minutes. To the solution is further added anequimolar amount or a slight excess, with reference to ureidointermediate (23), of a bromoacetamide derivative (25), followed bystirring at room temperature for several tens of minutes. Aftercompletion of the reaction, water is added to the reaction mixture, andthe mixture is extracted with an appropriate solvent, such as diethylether. The extract is dried and concentrated under reduced pressure. Theresidue is purified by a proper method to give monourea compound (19).

The preparation of N-substituted isatin (3) according to Reaction Route8 can preferably be carried out as follows. Indole (32) is dissolved ina solvent giving no adverse influence to the reaction, such as dryN,N-dimethylformamide or dry tetrahydrofuran, preferably dry dimethylsulfoxide, and a solution of an equimolar amount or an excess, withreference to indole (32), of a base, such as sodium hydride or potassiumt-butoxide, in dry dimethyl sulfoxide, is added thereto at roomtemperature, followed by stirring at room temperature for 10 minutes to1 hour. An equimolar amount or an excess molar amount, with reference toindole (32), of a halide is then added thereto, followed by stirring atroom temperature or under heating for several tens of minutes to 10hours. After completion of the reaction, water is added to the reactionmixture, followed by extraction with an appropriate solvent, such asdiethyl ether. The extract is dried and concentrated under reducedpressure to give 1-substituted indole (33). The resulting crude productmay be used in the next reaction or may be purified by a proper method.Then, 1-substituted indole (33) and, as a proton source, excesspotassium dihydrogenphosphate or sodium dihydrogenphosphate aresuspended in an appropriate solvent, such as ethyl acetate, and anaqueous solution of excess sodium hypochlorite is added thereto at roomtemperature or under ice-cooling, followed by stirring at thattemperature for 5 to 30 minutes. After completion of the reaction, thereaction mixture is washed successively with water and a base, dried,and concentrated to give dichloro compound (34). The resulting crudeproduct may be used in the subsequent reaction or may be purified by aproper method. Dichloro compound (34) is dissolved in an appropriatesolvent, such as dimethyl sulfoxide, and excess base suitable forhydrolysis, for example, an aqueous solution of sodium hydroxide, isadded thereto dropwise, followed by stirring for 10 minutes to 1 hour.To the mixture is slowly added an acid, e.g., concentrated hydrochloricacid, in excess over the base previously added, followed by stirring atroom temperature for several hours. To the reaction mixture is addedethyl acetate, and the mixture is washed successively with water and abase. The organic layer is dried and concentrated to give N-substitutedisatin (3). The resulting crude product can be used as an intermediatein Reaction Route 5 either without purification or after being purifiedby a proper method.

Of monourea compounds (19), those containing an acetal group or an aminogroup in the substituent at the 1-position can be prepared by theprocesses shown in Reaction Routes 4 and 5. In addition, monoureacompound (19) containing acetal at the 1-substituent, i.e., monoureacompound (28) can be prepared by acetal exchange from another acetalcompound or by hydrolyzing the another acetal compound to once givealdehyde compound (27) which is then converted to acetal compound (28).Monourea compound (19) containing an amino group at the 1-substituent,i.e., monourea compound (29) can be prepared by reductive aminationreaction of aldehyde compound (27).

The preparation of monourea compound (28) containing acetal at the1-substituent can preferably be carried out as follows. Acetal compound(26) prepared by the process shown in Reaction Route 4 or 5 is dissolvedin an alcohol for acetal exchange and stirred for 6 hours to 2 dayswhile heating in the presence of an appropriate acid, such asp-toluenesulfonic acid, sulfuric acid or camphorsulfonic acid, as acatalyst. The reaction mixture is concentrated, and an appropriate base,for example, an aqueous solution of sodium hydrogencarbonate, is addedthereto, followed by extraction with an appropriate organic solvent. Theextract is dried and concentrated under reduced pressure. The residue ispurified by a proper method to obtain (28). Alternatively, (26) isdissolved or suspended in an inert solvent, such as acetone, an alcohol,water or a mixture thereof, and an adequate amount of an appropriateacid, such as p-toluenesulfonic acid, sulfuric acid or camphorsulfonicacid, is added thereto, followed by stirring at room temperature orunder heating for 1 to 18 hours. The reaction mixture is concentrated,an appropriate base, e.g., a sodium hydrogencarbonate aqueous solution,is added thereto, the mixture is extracted with an appropriate organicsolvent, and the extract is dried and concentrated under reducedpressure to give aldehyde compound (27). This crude product may be usedin the subsequent reaction without purification or after being purifiedby a proper method. Aldehyde compound (27) and an appropriate alcohol ordiol in excess over aldehyde compound (27) are dissolved or suspended inan inert solvent, preferably toluene or benzene, and stirred in thepresence of an appropriate acid catalyst, such as p-toluenesulfonicacid, sulfuric acid or camphorsulfonic acid, for 6 to 48 hours underheating while azeotropically removing produced water together with thesolvent. The reaction mixture is washed with an appropriate base, suchas an aqueous solution of sodium hydrogencarbonate, dried, andconcentrated. The concentrate is purified by a proper method to giveacetal compound (28).

The preparation of monourea compound (28) containing an amino group atthe 1-substituent can preferably be carried out as follows. Aldehydecompound (27) and an equivalent or excess of an amine or an aqueoussolution thereof are dissolved in an inert solvent, such as methanol.After neutralizing the solution with an appropriate acid, such as aceticacid, trifluoroacetic acid or hydrochloric acid, an equivalent orexcess, with reference to (27), of a hydrogenating agent, such as sodiumcyanoborohydride, is added to the solution, followed by stirring at roomtemperature for 4 to 48 hours. The reaction mixture is concentrated,water is added thereto, the mixture is extracted with an appropriateorganic solvent. The extract is dried and concentrated, and the residueis purified by a proper method to give amino compound (29).

The preparation of monourea compound (30) containing thioacetal in the1-substituent can preferably be carried out as follows. Acetal compound(26) prepared by the process shown in Reaction Route 4 or 5 is dissolvedin an inert solvent, such as dry tetrahydrofuran, acetonitrile ordichloromethane, preferably dichloromethane. A mercaptan in an amount of2 mol per mol of (26) or in excess over (26) and 2 equivalents, withreference to acetal (26), of an appropriate Lewis acid, such as borontrifluoride ethyl etherate, are added to the solution at roomtemperature or a low temperature, followed by stirring at roomtemperature for 10 minutes to 2 hours. The reaction mixture isconcentrated, an appropriate base, such as 1N sodium hydroxide, is addedthereto, and the mixture is extracted with an appropriate organicsolvent. The extract is dried and concentrated under reduced pressure,and the residue is purified by a proper method to give (30).

Each enantiomer of monourea compound (19) can be prepared bystereospecifically bonding an optically active acetic ester to racemicureido intermediate (23) to give (31), which is recrystallized to give asingle diastereomer, hydrolyzing the diastereomer, and converting theresulting carboxylic acid to an amide as shown in Reaction Route 7. Thesingle diastereomer of (31) can also be obtained by once preparing adiastereomer mixture of (31) by nonselective addition of an opticallyactive acetic ester to racemic ureido intermediate (23) or byesterification of racemic carboxylic acid intermediate (18) and thenresolving the mixture by recrystallization from an appropriate solvent.

The preparation of each enantiomer of monourea compound (19) by ReactionRoute 7 can preferably be carried out as follows. Ureido intermediate(23) is dissolved in a solvent giving no adverse influence to thereaction, preferably dry tetrahydrofuran or dry dioxane, under anitrogen atmosphere, and an equivalent, with reference to (23), of alithium agent, such as an alkyl lithium, lithium amide or a lithiumalkoxide, is added thereto at a low temperature, followed by stirring ata low temperature for 1 to 30 minutes. Additionally, an equivalent, withreference to (23), of an optically active bromoacetic ester, preferablyL- or D-menthyl bromoacetate is added thereto at a low temperature,followed by stirring at -10° C. to room temperature for 4 to 24 hours.Water is added to the reaction mixture, and the mixture is extractedwith an appropriate organic solvent. The extract is dried andconcentrated, and the residue is recrystallized 1 to 5 times from anappropriate solvent, such as ethyl ether, isopropyl ether, hexane, analcohol, water or a mixture thereof, to give a single diastereomer of(31). The optical purity of (31) can be analyzed by high performanceliquid chromatography, high resolution nuclear magnetic resonancespectrum, and the like. Subsequently, the single diastereomer of (31) ishydrolyzed in the same manner as in the preparation of carboxylic acid(17) in Reaction Route 4 to obtain optically active intermediate (18)common to both reaction routes, which is then led to optically activemonourea compound (19) in the same manner as in Reaction Route 4.

The present invention will now be illustrated in greater detail by wayof Examples, but it should be understood that the present invention isnot deemed to be limited thereto.

REFERENCE EXAMPLE 1 3,3-Dimethoxyindolin-2-one

In 500 ml of methanol were dissolved 14.7 g of isatin and 10.6 g oftrimethyl orthoformate, and 100 mg of p-toluenesulfonic acid was addedthereto. The mixture was heated under reflux for 7 hours, followed byconcentration. To the residue was added chloroform, and the mixture waswashed with saturated aqueous sodium hydrogencarbonate. The organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresulting crude product was purified by silica gel column chromatography(eluent: chloroform/ethyl acetate=10/1) to give 14.7 g (76%) of thetitle compound as an oil.

Rf=0.38 (chloroform/methanol=20/1)

IR (CCl₄): 1735, 1629, 1475 cm⁻¹

NMR (CDCl₃) δ: 8.16 (br, 1H), 7.42-7.26 (m,2H), 7.07 (ddd, J=1.0, 7.3,7.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.58 (s, 6H).

MS (m/e): 193 (M⁺), 165, 162, 120, 92

REFERENCE EXAMPLE 2 3,3-Diethoxyindolin-2-one

In 500 ml of ethanol were dissolved 14.7 g of isatin and 10.6 g oftriethyl orthoformate, and 100 mg of camphorsulfonic acid was addedthereto. The mixture was heated under reflux for 12 hours, followed byconcentration. To the residue was added chloroform, and the mixture waswashed with saturated aqueous sodium hydrogencarbonate. The organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresulting crude product was purified by silica gel column chromatography(chloroform/ethyl acetate=10/1) to give 20.4 g (92%) of the titlecompound as an oil.

Rf=0.50 (chloroform/methanol=20/1)

NMR (CDCl₃) δ: 8.40 (br, 1H), 7.46-6.81 (m, 4H), 4.09-3.53 (m, 4H), 1.26(t, J=7 Hz, 6H).

REFERENCE EXAMPLE 3 N-Benzylisatin

A solution of 44 g of isatin in 200 ml of N,N-dimethylformamide wasadded dropwise to a suspension of 16.0 g of sodium hydride (60%) in 100ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After themixture was stirred at that temperature for 30 minutes, a solution of61.5 g of benzyl bromide in 100 ml of N,N-dimethylformamide was addedthereto. The whole mixture was stirred for 1 hour and then concentrated.Chloroform was added to the residue, and the mixture was washed withsaturated aqueous sodium hydrogencarbonate. The organic layer was driedover anhydrous sodium sulfate and concentrated. The resulting crudeproduct was washed with hexane and recrystallized from ethanol to give47.3 g (67%) of the title compound as red needles.

Rf=0.22 (n-hexane/ethyl acetate=5/1)

NMR (CDCl₃) δ: 7.59-8.27 (m, 7H), 7.11-7.04 (m, 1H), 6.75 (d, J=7.8 Hz,1H), 5.93 (s, 2H).

REFERENCE EXAMPLE 4 1-Benzyl-3,3-dimethoxyindolin-2-one

The title compound was obtained in the same manner as in ReferenceExample 1, except for starting with N-benzylisatin.

Rf=0.33 (n-hexane/ethyl acetate=5/1).

NMR (CDCl₃) δ: 7.41 (d, J=6.8 Hz, 1H), 7.28-7.19 (m, 6H), 7.04 (t, J=7.8Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 4.86 (s, 2H), 3.60 (s, 6H).

MS (m/e): 283 (M⁺), 252, 210, 192, 132, 91

REFERENCE EXAMPLE 5 3,3-Dimethoxy-5-nitroindolin-2-one

The title compound was obtained in the same manner as in ReferenceExample 1, except for starting with 5-nitroisatin.

Rf=0.32 (chloroform/methanol=20/1)

NMR (CDCl₃) δ: 8.32 (s, 1H), 7.36-7.26 (m, 2H), 7.01 (d, J=9.2 Hz, 1H),3.62 (s, 6H).

MS (m/e): 238 (M⁺), 210, 180, 165

REFERENCE EXAMPLE 6 3,3-Dimethoxy-1-phenylindolin-2-one

The title compound was obtained in the same manner as in ReferenceExample 1, except for starting with N-phenylisatin.

Rf=0.38 (n-hexane/ethyl acetate=5/1)

NMR (CDCl₃) δ: 7.60-6.72 (m, 9H), 3.64 (s, 6H).

MS (m/e): 269 (M⁺), 241, 208, 195, 180, 166

REFERENCE EXAMPLE 7 1-Allyl-3,3-dimethoxyindolin-2-one

A solution of 3.86 g of 3,3-dimethoxyindolin-2-one in 30 ml ofN,N-dimethylformamide was added dropwise to a suspension of 1.2 g ofsodium hydride (60%) in 40 ml of N,N-dimethylformamide at 0° C. in anitrogen stream. After the mixture was stirred at that temperature for30 minutes, 2.60 ml of allyl bromide was added thereto. The resultingmixture was stirred for 1 hour and then concentrated. Chloroform wasadded to the residue, and the mixture was washed with an aqueoussolution of sodium chloride. The organic layer was dried over anhydroussodium sulfate and concentrated. The resulting crude product waspurified by silica gel column chromatography (chloroform/hexane=1/1) togive 4.19 g (90%) of the title compound.

Rf=0.85 (chloroform/methanol=20/1)

NMR (CDCl₃) δ: 7.52-6.71 (m, 4H), 6.20-5.55 (m, 1H), 5.41-5.00 (m, 2H),4.30 (d, J=5 Hz, 2H), 3.57 (s, 6H).

REFERENCE EXAMPLE 8 3,3-Dimethoxy-1-(2,2-dimethoxyethyl)indolin-2-one

A solution of 34.3 g of 3,3-dimethoxyindolin-2-one in 400 ml ofN,N-dimethylformamide was added dropwise to a suspension of 8.56 g ofsodium hydride (60%) in 100 ml of N,N-dimethylformamide at 0° C. in anitrogen stream. After the mixture was stirred at that temperature for30 minutes, 36.2 g of bromoacetaldehyde dimethyl acetal was addedthereto. The resulting mixture was stirred at 80° C. for 1 day and thenconcentrated. Ethyl acetate was added to the residue, and the mixturewas washed with an aqueous solution of sodium chloride. The organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresulting crude product was recrystallized from isopropyl alcohol/hexaneto give 25.1 g (50%) of the title compound.

Rf=0.43 (n-hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.51-6.90 (m, 4H), 4.59 (t, J=5.5 Hz, 1H), 3.77 (d, J=5.5Hz, 2H), 3.55 (s, 6H), 3.40 (s, 6H).

REFERENCE EXAMPLE 9 1-(2,2-Diethoxyethyl)-3,3-dimethoxyindolin-2-one

The title compound was obtained in the same manner as in ReferenceExample 8, except for using bromoacetaldehyde diethyl acetal as areactant.

Rf=0.71 (chloroform/methanol=20/1)

NMR (CDCl₃) δ: 7.48-6.70 (m, 4H), 4.66 (t, J=5 Hz, 1H), 3.78-3.28 (m,6H), 3.52 (s, 6H), 1.12 (t, J=7 Hz, 6H).

MS (m/e): 309 (M⁺), 232, 178, 132, 103

REFERENCE EXAMPLE 10 3,3-Diethoxy-1-(2,2-diethoxyethyl)indolin-2-one

The title compound was obtained in the same manner as in ReferenceExample 8, except for using 3,3-diethoxyindolin-2-one as a startingmaterial and bromoacetaldehyde diethyl acetal as a reactant.

NMR (CDCl₃) δ: 7.39-7.26 (m, 2H), 7.09-7.01 (m, 2H), 4.71 (t, J=5.4 Hz,1H), 3.95-3.67 (m, 8H), 3.57-3.43 (m, 2H), 1.22 (t, J=7.4 Hz, 6H), 1.12(t, J=7.4 Hz, 6H).

REFERENCE EXAMPLE 113,3-Di-n-propoxy-1-(2,2-di-n-propoxyethyl)indolin-2-one

To a solution of 7.18 g of3,3-dimethoxy-1-(2,2-dimethoxyethyl)indolin-2-one in 200 ml ofn-propanol was added 0.1 g of camphorsulfonic acid, and the mixture washeat-refluxed for 4 days. The reaction mixture was concentrated,dichloromethane was added to the residue, and the mixture was washedwith saturated aqueous sodium hydrogencarbonate. The organic layer wasdried over anhydrous sodium sulfate and concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate=10/1)to yield 9.35 g (93%) of the title compound as a colorless oil.

NMR (CDCl₃) δ: 7.45-6.85 (m, 4H), 4.67 (t, J=5 Hz, 1H), 3.85-3.18 (m,10H), 1.82-1.16 (m, 8H), 1.10-0.67 (m, 12H).

MS (m/e): 393 (M⁺), 334, 232, 162, 131, 89

Example 1 1-Benzyl-3,3-bis(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.80 g of anhydrous aluminum chloride in 20 ml of drytetrahydrofuran were added successively a solution of 0.57 g of1-benzyl-3,3-dimethoxyindolin-2-one in 10 ml of dry tetrahydrofuran and0.60 g of p-tolylurea at 0° C. under a nitrogen atmosphere, and themixture was heated under reflux for 2 hours. Ethyl acetate was added tothe reaction mixture, and the mixture was washed twice with an aqueoussolution of sodium chloride. The organic layer was dried over anhydroussodium sulfate, followed by concentration. The residue was purified bysilica gel column chromatography (chloroform/ethyl acetate=4/1) toobtain 0.24 g (23%) of1-benzyl-3,3-bis(N'-(4-methylphenyl)ureido)indolin-2-one as a whitepowder.

Rf=0.49 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 8.71 (s, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.44-7.13 (m,17H), 6.76 (d, J=7.8 Hz, 1H), 4.96 (s, 2H), 2.21 (s, 6H).

FAB MS: 520 (M+H)⁺, 370, 263, 237, 147, 107

Example 2 3,3-Bis(N'-(4-methylphenyl)ureido)-5-nitroindolin-2-one

The title compound was prepared in the same manner as in Example 1,except for replacing 1-benzyl-3,3-dimethoxyindolin-2-one used in Example1 as a starting material with 3,3-dimethoxy-5-nitroindolin-2-one.

NMR (DMSO-d₆) δ: 11.32 (br, 1H), 8.69 (s, 2H), 8.64 (d, J=2.4 Hz, 1H),8.18 (dd, J=2.4, 8.8 Hz, 1H), 7.38 (s, 2H), 7.29-6.99 (m, 9H), 2.21 (s,6H).

EXAMPLES 3 TO 7

The following compounds were prepared in the same manner as in Example1, except for replacing 1-benzyl-3,3-dimethoxyindolin-2-one used inExample 1 as a starting material with 3,3-dimethoxyindolin-2-one havinga different substituent at the 1-position thereof.

Example 3 1-Allyl-3,3-bis(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.70 (s, 2H), 7.83 (d, J=6.8 Hz, 1H), 7.27-6.89 (m,13H), 5.90-5.81 (m, 1H), 5.38 (d, J=16.1 Hz, 1H), 5.20 (d, J=8.8 Hz,1H), 4.37 (br, 2H), 2.21 (s, 6H).

Example 4 3,3-Bis(N'-(4-methylphenyl)ureido)-1-phenylindolin-2-one

Rf=0.37 (CHCl₃ /AcOEt=5/1)

NMR (DMSO-d₆) δ: 8.74 (s, 2H), 7.91 (d, J=6.3 Hz, 1H), 7.65-7.01 (m,17H), 6.68 (d, J=7.8 Hz, 1H), 2.21 (s, 6H).

Example 51-(2,2-Dimethoxyethyl)-3,3-bis(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.72 (s, 2H), 7.84 (d, J=7.3 Hz, 1H), 7.26-6.98 (m,13H), 4.63 (t, J=4.9 Hz, 1H), 3.81 (d, J=4.9 Hz, 2H), 3.36 (s, 6H), 2.20(s, 6H).

Example 63,3-Bis(N'-(4-methylphenyl)ureido)-1-(2,2-di-n-propoxyethyl)indolin-2-one

Rf=0.29 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃) δ: 7.82 (br, 2H), 7.63 (d, J=7.3 Hz, 1H), 7.26 (t, J=4.4 Hz,1H), 7.11 (d, J=8.3 Hz, 4H), 7.03-6.91 (m, 2H), 6.89 (d, J=8.3 Hz, 4H),6.68 (br, 2H), 4.76 (t, J=5.4 Hz, 1H), 3.85 (d, J=5.4 Hz, 2H), 3.69-3.42(m, 4H), 2.20 (s, 6H), 1.52 (q, J=7.3 Hz, 4H), 0.82 (t, J=7.3 Hz, 6H).

Example 7(RS)-1-(2-Ethoxy-2-methoxyethyl)-3,3-bis(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.79 (br, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.26-6.82 (m,13H), 4.77 (t, J=5.6 Hz, 1H), 3.87-3.53 (m, 4H), 3.41 (s, 3H), 2.16 (s,6H), 1.13 (t, J=7.1 Hz, 3H).

Example 8 3,3-Bis(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 12.0 g of anhydrous aluminum chloride in 150 ml of drytetrahydrofuran were added successively a solution of 5.79 g ofisatin-3,3-dimethylacetal in 150 ml of dry tetrahydrofuran and 9.0 g ofp-tolylurea at 0° C. under a nitrogen atmosphere, and the mixture washeated under reflux for 40 minutes. Ethyl acetate was added to thereaction mixture, and the mixture was washed twice with an aqueoussolution of sodium chloride. The organic layer was dried over anhydroussodium sulfate, followed by concentration. To the residue was added 150ml of ethyl ether, and insoluble matter was removed by filtration. Thefiltrate was concentrated and recrystallized from acetone to yield 4.61g (36%) of the title compound as a white powder.

Rf=0.38 (chloroform/ethyl acetate=1/2)

NMR (DMSO-d₆) δ: 10.57 (s, 1H), 8.68 (s, 2H), 7.77 (d, J=7.8 Hz, 1H),7.21-7.14 (m, 7H), 7.02-6.79 (m, 6H), 2.21 (s, 6H).

FAB MS: 430 (M+H)⁺, 280, 147

IR (KBr): 3350, 1730, 1675, 1652, 1607, 1548, 1515, 1314, 1242 cm⁻¹

Example 9 3,3-Bis(N'-phenylureido)indolin-2-one

The title compound was prepared in the same manner as in Example 8,except for starting with phenylurea in place of p-tolylurea used inExample 8. Yield: 28%.

Rf=0.31 (chloroform/ethyl acetate=1/2)

NMR (DMSO-d₆) δ: 10.61 (s, 1H), 8.80 (s, 2H), 7.78 (d, J=7.8 Hz, 1H),7.33-7.16 (m, 11H), 6.94-6.79 (m, 4H).

Example 101-(2,2-Diethoxyethyl)-3,3-bis(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 4.00 g of anhydrous aluminum chloride in 30 ml of drytetrahydrofuran were added successively a solution of 3.37 g ofN-(2,2-diethoxyethyl)isatin-3,3-diethylacetal in 30 ml of drytetrahydrofuran and 3.01 g of p-tolylurea at 0° C. in a nitrogen stream,and the mixture was heated under reflux for 2 hours. Ethyl acetate wasadded to the reaction mixture, and the mixture was washed twice with anaqueous solution of sodium chloride. The organic layer was dried overanhydrous sodium sulfate, followed by concentration. The residue waschromatographed on silica gel (chloroform/methanol=50/1) andrecrystallized from ethyl ether to afford 0.744 g (14%) of the titlecompound as a white powder.

Rf=0.44 (chloroform/methanol=20/1)

NMR (CDCl₃) δ: 7.79 (br, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.26-6.82 (m,13H), 4.77 (t, J=4.9 Hz, 1H), 3.82-3.57 (m, 6H), 2.16 (s, 6H), 1.13 (t,J=7.1 Hz, 6H).

EXAMPLES 11 TO 21

The following compounds were prepared in the same manner as in Example10, except for replacing p-tolylurea used in Example 10 with variousarylureas.

Example 111-(2,2-Diethoxyethyl)-3,3-bis(N'-(4-methoxyphenyl)ureido)indolin-2-one

Rf=0.33 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃) δ: 7.73 (br, 2H), 7.70 (d, J=7.3 Hz, 1H), 7.28 (t, J=7.8 Hz,1H), 7.12 (d, J=9.2 Hz, 4H), 7.08-6.96 (m, 2H), 6.67 (br, 2H), 6.64 (d,J=9.2 Hz, 4H), 4.77 (t, J=4.8 Hz, 1H), 3.86 (d, J=4.8 Hz, 2H), 3.81-3.49(m, 4H), 3.68 (s, 6H), 1.12 (t, J=7.3 Hz, 6H).

Example 121-(2,2-Diethoxyethyl)-3,3-bis(N'-(4-methoxycarbonylphenyl)ureido)indolin-2-one

Rf=0.15 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃) δ: 8.17 (s, 2H), 7.83 (d, J=7.8 Hz, 1H), 7.63 (d, J=8.3 Hz,4H), 7.33-7.17 (m, 7H), 7.10-6.97 (m, 2H), 4.84 (t, J=4.9 Hz, 1H), 3.81(s, 6H), 3.85-3.60 (m, 6H), 1.16 (t, J=6.8 Hz, 6H).

Example 133,3-Bis(N'-(4-cyanophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

Rf=0.16 (CHCl₃ /MeOH=20/1)

NMR (DMSO-d₆) δ: 9.30 (s, 2H), 7.84 (d, J=7.4 Hz, 1H), 7.67-7.46 (m,10H), 7.29 (t, J=7.4 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.01 (t, J=7.8 Hz,1H), 4.73 (t, J=5.4 Hz, 1H), 3.80 (d, J=5.4 Hz, 2H), 3.73-3.49 (m, 4H),1.08 (t, J=7.4 Hz, 6H).

Example 14

1-(2,2-Diethoxyethyl)-3,3-bis(N'-(4-fluorophenyl)ureido)indolin-2-one

Rf=0.22 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃) δ: 7.88 (s, 2H), 7.79 (d, J=6.8 Hz, 1H), 7.31 (t, J=6.8 Hz,1H), 7.17-6.97 (m, 8H), 6.75 (t, J=8.8 Hz, 4H), 4.79 (t, J=5.3 Hz, 1H),3.85 (d, J=5.3 Hz, 2H), 3.79-3.56 (m, 4H), 1.13 (t, J=7.8 Hz, 6H).

Example 151-(2,2-Diethoxyethyl)-3,3-Bis(N'-(3-fluorophenyl)ureido)indolin-2-one

Rf=0.27 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃) δ: 8.01 (s, 2H), 7.82 (d, J=7.3 Hz, 1H), 7.35-6.90 (m, 10H),6.82 (d, J=7.3 Hz, 1H), 6.57 (t, J=7.3 Hz, 2H), 4.82 (t, J=4.8 Hz, 1H),3.88 (d, J=4.8 Hz, 2H), 3.83-3.60 (m, 4H), 1.15 (t, J=6.8 Hz, 6H).

Example 161-(2,2-Diethoxyethyl)-3,3-bis(N'-(4-nitrophenyl)ureido)indolin-2-one

Rf=0.21 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃ -DMSO-d₆) δ: 9.24 (s, 2H), 8.07 (d, J=9.5 Hz, 4H), 7.95 (d,J=6.3 Hz, 1H), 7.50 (d, J=9.5 Hz, 4H), 7.45 (s, 2H), 7.30 (t, J=7.8 Hz,1H), 7.12-7.02 (m, 2H), 4.82 (t, J=5.4 Hz, 1H), 3.91 (d, J=5.4 Hz, 2H),3.81-3.65 (m, 4H), 1.17 (t, J=6.8 Hz, 6H).

Example 171-(2,2-Diethoxyethyl)-3,3-bis(N'-(4-trifluoromethylphenyl)ureido)indolin-2-one

Rf=0.29 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃) δ: 8.03 (br, 2H), 7.86 (d, J=7.8 Hz, 1H), 7.46-6.95 (m,13H), 4.84 (t, J=5.4 Hz, 1H), 3.90-3.61 (m, 6H), 1.27-1.12 (m, 6H).

Example 181-(2,2-Diethoxyethyl)-3,3-bis(N'-(2-fluorophenyl)ureido)indolin-2-one

Rf=0.35 (n-hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.89-7.82 (m, 3H), 7.71 (s, 2H), 7.28 (t, J=6.1 Hz, 1H),7.18 (br, 2H), 7.10-6.98 (m, 2H), 6.89-6.78 (m, 6H), 4.82 (t, J=5.3 Hz,1H), 3.91 (d, J=5.3 Hz, 2H), 3.82-3.71 (m, 2H), 3.67-3.58 (m, 2H), 1.13(t, J=6.9 Hz, 6H).

Example 193,3-Bis(N'-(2-cyanophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

Rf=0.25 (n-hexane/ethyl acetate=2/1)

NMR (CDCl₃ -DMSO-d₆) δ: 8.79 (s, 2H), 8.30 (s, 2H), 8.17 (d, J=8.3 Hz,2H), 7.98 (d, J=5.6 Hz, 1H), 7.49-7.38 (m, 4H), 7.27 (dt, J=1.3, 6.3 Hz,1H), 7.09-6.95 (m, 4H), 4.79 (t, J=5.3 Hz, 1H), 3.89 (d, J=5.3 Hz, 2H),3.79-3.73 (m, 2H), 3.63-3.53 (m, 2H), 1.17 (t, J=6.9 Hz, 6H).

Example 203,3-Bis(N'-(4-bromophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

Rf=0.48 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃ -DMSO-d⁶) δ: 8.65 (s, 2H), 7.84 (d, J=7.3 Hz, 1H), 7.30-7.25(m, 10H), 7.10-6.96 (m, 3H), 4.79 (t, J=5.3 Hz, 1H), 3.88 (d, J=5.3 Hz,2H), 3.81-3.48 (m, 4H), 1.17-1.12 (m, 6H).

Example 213,3-Bis(N'-(3-bromophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

Rf=0.48 (CHCl₃ /MeOH=20/1)

NMR (CDCl₃) δ: 7.99 (br, 2H), 7.82 (d, J=7.6 Hz, 1H), 7.57 (s, 2H),7.33-7.24 (m, 3H), 7.09-6.93 (m, 6H), 6.96-6.80 (m, 2H), 4.86 (t, J=5.0Hz, 1H), 3.88 (d, J=5.0 Hz, 2H), 3.84-3.62 (m, 4H), 1.19-1.12 (m, 6H).

REFERENCE EXAMPLE 12 3,3-Bis(ethoxycarbonylmethyl)indolin-2-one

To a solution of 1.33 g of oxindole in 20 ml of dry dimethyl sulfoxidewas added 10 ml of a 1M solution of potassium t-butoxide in dry dimethylsulfoxide at room temperature under a nitrogen atmosphere, followed bystirring for 10 minutes. To the resulting mixture was added dropwise1.11 ml of ethyl bromoacetate, followed by stirring at the sametemperature for 20 minutes. To the mixture was further added 10 ml of a1M solution of potassium t-butoxide in dry dimethyl sulfoxide, followedby stirring for 10 minutes. To the mixture was added dropwise 1.11 ml ofethyl bromoacetate. The resulting mixture was stirred at the sametemperature for 20 minutes. The reaction mixture was treated with asodium chloride aqueous solution and extracted with ethyl ether. Theethyl ether layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1) to afford 0.79 g (26%) of thetitle compound.

Rf=0.22 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.87 (s, 1H), 7.30-7.18 (m, 2H), 7.04-6.86 (m, 2H),4.03-3.91 (m, 4H), 3.03 (d, J=16.1 Hz, 2H), 2.88 (d, J=16.1 Hz, 2H),1.07 (t, J=7.3 Hz, 6H).

MS (m/e): 305 (M⁺), 232, 186, 174, 146, 130

REFERENCE EXAMPLE 133,3-Bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one

The title compound was prepared in the same manner as in ReferenceExample 12, except for starting with t-butyl bromoacetate in place ofethyl bromoacetate used in Reference Example 12.

Rf=0.29 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 9.03 (br, 1H), 7.42-6.80 (m, 4H), 2.83 (s, 4H), 1.19 (s,18H).

MS (m/e): 361 (M⁺), 249, 204, 191, 145

REFERENCE EXAMPLE 14 3,3-Bis(hydroxycarbonylmethyl)indolin-2-one

To a solution of 0.73 g of 3,3-bis(ethoxycarbonylmethyl)indolin-2-one in40 ml of ethanol was added a solution of 1.25 g of potassium hydroxide(85%) in 5 ml of water at room temperature, and the mixture was stirredat that temperature for 15 hours, followed by concentration. Theconcentrate was dissolved in water, washed with chloroform, adjusted topH 2 with 10% hydrochloric acid, and concentrated. Ethyl acetate wasadded to the residue, and any insoluble matter was removed byfiltration. The filtrate was concentrated and purified by LH-20 columnchromatography (eluent: methanol). Yield: 86%.

Rf=0.27 (chloroform/methanol 1/1)

NMR (DMSO-d₆) δ: 12.14 (br, 2H), 10.35 (s, 1H), 7.27 (d, J=7.2 Hz, 1H),7.17-7.09 (m, 1H), 6.92-6.76 (m, 2H), 2.88 (d, J=16.0 Hz, 2H), 2.64 (d,J=16.0 Hz, 2H).

Example 22 3,3-Bis((4-methylphenyl)carbamoylmethyl)indolin-2-one

To a solution of 0.25 g of 3,3-bis(hydroxycarbonylmethyl)indolin-2-oneand 1.24 g of dicyclohexylcarbodiimide in 30 ml of N,N-dimethylformamidewere added successively 0.92 g of 1-hydroxybenzotriazole and 0.64 g ofp-toluidine at room temperature. The resulting mixture was stirred atroom temperature for 12 hours and concentrated. Ethyl acetate was addedto the residue, and the mixture was washed successively with dilutehydrochloric acid and saturated aqueous sodium hydrogencarbonate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The crude product was applied on silica gel column chromatography(chloroform/methanol 50/1) and then recrystallized from benzene to give0.54 g (63%) of the title compound as a white powder.

NMR (DMSO-d₆) δ: 10.32 (s, 1H), 9.77 (s, 2H), 7.33-6.81 (m, 12H), 3.09(d, J=14.9 Hz, 2H), 2.72 (d, J=14.9 Hz, 2H), 2.21 (s, 6H).

MS (m/e): 427 (M⁺), 321, 293, 172, 159, 107

Example 231-Benzyl-3,3-bis((4-methylphenyl)carbamoylmethyl)indolin-2-one

To a suspension of 0.05 g of sodium hydride (60%) in 5 ml ofN,N-dimethylformamide was added dropwise a solution of 0.36 g of3,3-bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one in 5 ml ofN,N-dimethylformamide at 0° C. in a nitrogen stream. After stirring themixture at that temperature for 30 minutes, 0.12 ml of benzyl bromidewas added thereto. The whole mixture was stirred for 1 hour and thenconcentrated. Chloroform was added to the concentrate, and the mixturewas washed with an aqueous solution of sodium chloride. The organiclayer was dried over anhydrous sodium sulfate and concentrated to obtain1-benzyl-3,3-bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one.

Rf=0.66 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.35-6.50 (m, 9H), 4.89 (s, 2H), 3.04-2.78 (m, 4H), 1.17(s, 18H).

The above-prepared1-benzyl-3,3-bis((1,1-dimethylethoxy)carbonylmethyl)indolin-2-one wasdissolved in 15 ml of ethanol, and to the solution was added a solutionof 0.66 g of potassium hydroxide (85%) in 2 ml of water at roomtemperature. The resulting mixture was heated under reflux for 5 hours,followed by concentration. The residue was dissolved in water, washedwith chloroform, and adjusted to pH 2 with 10% hydrochloric acid. Theresulting product was extracted with ethyl acetate, and the organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresidue was dissolved in 10 ml of chloroform, and 0.62 g ofdicyclohexylcarbodiimide, 0.46 g of 1-hydroxybenzotriazole, and 0.32 gof p-toluidine were successively added to the solution, followed bystirring at room temperature for 5 hours. The resulting precipitateswere removed by filtration, and the filtrate was washed successivelywith dilute hydrochloric acid and saturated aqueous sodiumhydrogencarbonate. The organic layer was dried over anhydrous sodiumsulfate, and concentrated. The crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=1/1) to obtain 0.29 g (57%)of the title compound as a white powder.

Rf=0.26 (hexane/ethyl acetate=1/1)

NMR (CDCl₃) δ: 9.83 (s, 2H), 7.46-6.61 (m, 17H), 4.92 (s, 2H), 3.20 (d,J=15.1 Hz, 2H), 2.83 (d, J=15.1 Hz, 2H), 2.21 (s, 6H).

MS (m/e): 517 (M⁺), 411, 383, 369, 262, 107, 91

EXAMPLES 24 TO 26

The following compounds were prepared in the same manner as in Example23, except for replacing benzyl bromide used in Example 23 with variousalkyl halides.

Example 241-Methyl-3,3-bis((4-methylphenyl)carbamoylmethyl)indolin-2-one

Rf=0.16 (n-hexane/ethyl acetate=1/1)

NMR (DMSO-d₆) δ: 9.77 (s, 2H), 7.31-6.88 (m, 12H), 3.16 (s, 3H), 3.11(d, J=15.1 Hz, 2H), 2.74 (d, J=15.1 Hz, 2H), 2.21 (s, 6H).

MS (m/e): 441 (M⁺), 335, 307, 186, 107

Example 253,3-Bis((4-methylphenyl)carbamoylmethyl)-1-(phenylcarbonylmethyl)indolin-2-one

Rf=0.41 (n-hexane/ethyl acetate=1/1)

NMR (DMSO-d₆) δ: 9.91 (s, 2H), 8.14 (d, J=7.3 Hz, 2H), 7.73-6.86 (m,15H), 5.35 (s, 2H), 3.30 (d, J=16.1 Hz, 2H), 2.78 (d, J=16.1 Hz, 2H),2.22 (s, 6H).

MS (m/e): 545 (M⁺), 439, 411, 333, 290, 107

Example 263,3-Bis((4-methylphenyl)carbamoylmethyl)-1-(2-pyridylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.83 (s, 2H), 8.55 (d, J=4.9 Hz, 1H), 7.66-7.50 (m,2H), 7.38-7.01 (m, 11H), 6.89 (t, J=7.3 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H),4.98 (s, 2H), 3.20 (d, J=15.1 Hz, 2H), 2.84 (d, J=15.1 Hz, 2H), 2.21 (s,6H).

MS (m/e): 518 (M⁺), 412, 384, 237, 107, 92

REFERENCE EXAMPLE 15(RS)-1-Benzyl-3-(ethoxycarbonylmethyl)-3-hydroxyindolin-2-one

To a solution of 2.4 ml of 1,1,1,3,3,3-hexamethyldisilazane in 10 ml ofdry tetrahydrofuran was added dropwise 6.4 ml of a 1.59M hexane solutionof n-butyl lithium at -78° C. under a nitrogen atmosphere, followed bystirring at that temperature for 10 minutes. To the mixture was slowlyadded 0.976 ml of ethyl acetate, followed by stirring at -78° C. for 30minutes. To the mixture was further added a solution of 2.00 g of1-benzylisatin in 10 ml of dry tetrahydrofuran, followed by stirring atthat temperature for 1 hour. Water was added to the reaction mixture,and the product was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate to give 2.23 g (81%) of the titlecompound.

NMR (CDCl₃) δ: 7.45-6.55 (m, 9H), 4.84 (s, 2H), 4.12 (q, J=6.9 Hz, 2H),2.97 (s, 2H), 1.40 (br, 1H), 1.13 (t, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 16(RS)-1-Benzyl-3-hydroxy-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

To a solution of 0.254 g of p-toluidine in 10 ml of dry tetrahydrofuranwas added dropwise 1.3 ml of a 1.59M hexane solution of n-butyl lithiumat -78° C. under a nitrogen atmosphere, followed by stirring at thattemperature for 10 minutes. To the mixture was added a solution of 0.299g of 1-benzyl-3-(ethoxycarbonylmethyl)-3-hydroxyindolin-2-one in 5 ml ofdry tetrahydrofuran at -78° C., followed by stirring at that temperaturefor 30 minutes. Water was added to the reaction mixture, and the productwas extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=5/1) to give0.161 g (44%) of the title compound.

NMR (CDCl₃) δ: 8.38 (s, 1H), 7.47-6.92 (m, 12H), 6.67 (d, J=8.6 Hz, 1H),5.38 (s, 1H), 4.88 (d, J=16.0 Hz, 1H), 4.74 (d, J=16.0 Hz, 1H), 3.06 (d,J=14.9 Hz, 1H), 2.69 (d, J=14.9 Hz, 1H), 2.29 (s, 3H).

Example 27(RS)-1-Benzyl-3-((4-methylphenyl)aminocarbonylmethyl)-3-((4-methylphenyl)aminocarbonyloxa)indolin-2-one

To a solution of 0.155 g of1-benzyl-3-hydroxy-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-oneand 0.097 ml of p-tolyl isocyanate in 10 ml of dry tetrahydrofuran wasadded 10 mg of dibutyltin diacetate at room temperature under a nitrogenatmosphere, and the mixture was stirred at that temperature for 18hours. Water was added to the reaction mixture, and the product wasextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1) to give0.178 g (89%) of the title compound.

NMR (CDCl₃) δ: 9.42-9.12 (br, 1H), 7.60-6.88 (m, 17H), 6.68 (d, J=7.8Hz, 1H), 5.04 (d, J=14.8 Hz, 1H), 4.94 (d, J=14.8 Hz, 1H), 3.14 (d,J=15.2 Hz, 1H), 2.99 (d, J=15.2 Hz, 1H), 2.28 (s, 3H), 2.21 (s, 3H).

REFERENCE EXAMPLE 17 1-Benzyl-3-(hydroxyimino)indolin-2-one

To a suspension of 7.11 g of N-benzylisatin in 75 ml of ethanol wasadded a solution of 3.84 g of hydroxylamine hydrochloride and 3.84 g ofsodium acetate in 500 ml of water. The mixture was stirred at roomtemperature for 1 hour, followed by concentration. The residue waswashed with water and recrystallized from ethanol to give 6.11 g (81%)of the title compound as yellow crystals.

Rf=0.33 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 13.51 (br, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.39-7.26 (m,6H), 7.10-6.96 (m, 2H), 4.94 (s, 2H).

MS (m/e): 252 (M⁺), 235, 207, 91

REFERENCE EXAMPLE 18 (RS)-3-(N'-(4-Methylphenyl)ureido)indolin-2-one

To a suspension of 73.6 g of isatin in 1.2 l of ethanol was added asolution of 64.1 g of hydroxylamine hydrochloride and 64.1 g of sodiumacetate in 500 ml of water. The mixture was stirred at room temperaturefor 30 minutes and concentrated. The residue was washed with water andrecrystallized from ethanol to give 51.8 g (64%) of3-(hydroxyimino)indolin-2-one as yellow crystals.

Rf=0.41 (chloroform/methanol=10/1)

NMR (CDCl₃ /DMSO-d₆) δ: 12.52 (s, 1H), 7.39-6.81 (m, 4H).

MS (m/e): 162 (M⁺), 145, 117

A suspension of 4.86 g of 3-(hydroxyimino)indolin-2-one and 100 mg of 5%Rh/C in 300 ml of ethanol was stirred at room temperature under ahydrogen atmosphere for 1 day. The reaction mixture was filtered throughCerite, and the filtrate was concentrated. The concentrate was dissolvedin 300 ml of dichloromethane, and 4.16 ml of p-tolyl isocyanate wasadded thereto at 0° C. The mixture was stirred at that temperature for 2hours, whereupon a precipitate formed. The precipitate was collected byfiltration and washed with ethanol to obtain 7.59 g (90%) of the titlecompound.

NMR (DMSO-d₆) δ: 10.30 (s, 1H), 8.61 (s, 1H), 7.27-6.77 (m, 9H), 4.95(d, J=7.3 Hz, 1H), 2.21 (s, 3H).

MS (m/e): 281 (M⁺), 174, 148, 132, 107

REFERENCE EXAMPLE 19 (RS)-3-((4-Methylbenzyl)carbonylamino)indolin-2-one

A solution of 4.86 g of 3-(hydroxyimino)indolin-2-one and 100 mg of 5%Rh/C in 300 ml of ethanol was stirred at room temperature under ahydrogen atmosphere for 1 day. The reaction mixture was filtered throughCerite, and the filtrate was concentrated. The concentrate was dissolvedin 50 ml of N,N-dimethylformamide, and 5.15 g ofdicyclohexylcarbodiimide, 3.83 g of 1-hydroxybenzotriazole, and 3.75 gof p-tolylacetic acid were added thereto successively. The mixture wasstirred at the same temperature for 12 hours, whereupon a precipitateformed. The precipitate was filtered off, and the filtrate wasconcentrated. The concentrate was diluted with ethyl acetate and washedsuccessively with dilute hydrochloric acid and saturated aqueous sodiumhydrogencarbonate. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (chloroform/methanol=40/1) to afford 1.01 g (18%) of thetitle compound.

Rf=0.32 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 10.39 (s, 1H), 8.80 (d, J=8.3 Hz, 1H), 7.21-7.02 (m,6H), 6.91 (dd, J=1.0, 6.3 Hz, 1H), 6.79 (d, J=6.3 Hz, 1H), 5.08 (d,J=8.3 Hz, 1H), 3.44 (s, 2H), 2.27 (s, 3H).

MS (m/e): 280 (M⁺), 262, 148, 132, 105

REFERENCE EXAMPLE 20 (RS)-1-Benzyl-3-(methylcarbonylamino)indolin-2-one

A suspension of 2.52 g of 1-benzyl-3-(hydroxyimino)indolin-2-one and 100mg of 5% Rh/C in 200 ml of methanol was stirred under a hydrogenatmosphere at room temperature for 1 day. The reaction mixture wasfiltered through Cerite, and the filtrate was concentrated. The residuewas dissolved in 200 ml of dichloromethane, and 2.79 ml of triethylamineand 0.85 ml of acetyl chloride were successively added thereto at roomtemperature. The mixture was stirred at that temperature for 1 hour, andthen was washed successively with dilute hydrochloric acid and saturatedaqueous sodium hydrogencarbonate. The organic layer was dried overanhydrous sodium sulfate and concentrated. Recrystallization of theresidue from chloroform-hexane gave 1.28 g (45%) of the title compound.

Rf=0.30 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 8.79 (d, J=7.8 Hz, 1H), 7.41-7.13 (m, 7H), 6.98 (dd,J=6.8, 7.8 Hz, 1H), 6.76 (d, J=7.3 Hz, 1H), 5.22 (d, J=7.8 Hz, 1H), 4.97(d, J=15.8 Hz, 1H), 4.81 (d, J=15.8 Hz, 1H), 1.92 (s, 3H).

REFERENCE EXAMPLE 21 1-(2,2-Diethoxyethyl)isatin

A solution of 31.8 g of isatin in 300 ml of dry dimethyl sulfoxide wasadded dropwise to a suspension of 25.4 g of potassium t-butoxide in 200ml of dry dimethyl sulfoxide at 10° C. in a nitrogen stream. Afterstirring the mixture at that temperature for 30 minutes, 39 ml ofbromoacetaldehyde diethyl acetal was added thereto, followed by stirringat 70° C. for 6 hours. The reaction mixture was poured into dilutehydrochloric acid and extracted with ethyl ether. The organic layer wasdried over anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (chloroform/ethylacetate=20/1) to give 31.4 g (55%) of the title compound as a redpowder.

Rf=0.83 (chloroform/methanol=20/1)

NMR (CDCl₃) δ: 7.75-6.95 (m, 4H), 4.71 (t, J=5 Hz, 1H), 3.89-3.40 (m,6H), 1.16 (t, J=7 Hz, 6H).

Example 28(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

A solution of 5.38 g of hydroxylamine hydrochloride and 5.38 g of sodiumacetate in 40 ml of water was added to a suspension of 11.1 g of1-(2,2-diethoxyethyl)isatin in 100 ml of ethanol. The mixture wasstirred at room temperature for 1 hour, followed by concentration. Theconcentrate was diluted with chloroform and washed with an aqueoussolution of sodium chloride. The chloroform layer was dried overanhydrous sodium sulfate and concentrated, and the residue wasrecrystallized from ethyl acetate to obtain 7.10 g (61%) of1-(2,2-diethoxyethyl)-3-(hydroxyimino)indolin-2-one as yellow crystals.

Rf=0.32 (chloroform/methanol=20/1)

NMR (CDC₃ /DMSO-d₆) δ: 12.85 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.39-7.31(m, 1H), 7.08-7.01 (m, 2H), 4.70 (t, J=5.4 Hz, 1H), 3.84 (d, J=5.4 Hz,2H), 3.82-3.43 (m, 4H), 1.14 (t, J=6.8 Hz, 6H).

A suspension of 30.0 g of1-(2,2-diethoxyethyl)-3-(hydroxyimino)indolin-2-one and 200 mg of 5%Rh/C in 1.5 l of ethanol was stirred under a hydrogen atmosphere at roomtemperature for 2 days. The reaction mixture was filtered throughCerite, and the filtrate was concentrated. The residue was dissolved in600 ml of dichloromethane, and a solution of 15.0 ml of p-tolylisocyanate in 200 ml of dichloromethane was added thereto at 0° C. Themixture was stirred at that temperature for 1 hour, followed byconcentration. The resulting crude product was washed with ethyl etherto yield 30.8 g (72%) of the title compound as a white powder.

NMR (DMSO-d₆) δ: 8.63 (s, 1H), 7.33-7.16 (m, 4H), 7.12-6.87 (m, 5H),5.05 (d, J=7.4 Hz, 1H), 4.77-4.63 (m, 1H), 3.84 (dd, J=5.7, 14.6 Hz,1H), 3.77-3.40 (m, 5H), 2.22 (s, 3H), 1.08 (t, J=7.4 Hz, 3H), 1.06 (t,J=7.4 Hz, 3H).

EXAMPLES 29 TO 32

The following compounds were prepared in the same manner as in Example28, except for replacing 1-(2,2-diethoxyethyl)isatin used as a startingmaterial in Example 28 with various isatin derivatives.

Example 29 (RS)-1-Benzyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.70 (s, 1H), 7.39-7.00 (m, 13H), 6.78 (d, J=7.3 Hz,1H), 5.13 (d, J=7.3 Hz, 1H), 4.90 (s, 2H), 2.21 (s, 3H).

MS (m/e): 371 (M⁺), 238, 147, 107, 91

Example 30 (RS)-3-(N'-(4-Methylphenyl)ureido)-1-phenylindolin-2-one

NMR (DMSO-d₆) δ: 8.76 (s, 1H), 7.61-6.99 (m, 13H), 6.71 (d, J=7.3 Hz,1H), 5.20 (d, J=7.3 Hz, 1H), 2.22 (s, 3H).

MS (m/e): 357 (M⁺), 250, 223, 194, 180, 106

Example 31(RS)-1-(2,2-Diethoxyethyl)-5-methyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.62 (s, 1H), 7.25 (d, J=8.3 Hz, 2H), 7.06-6.86 (m,6H), 5.03 (d, J=7.8 Hz, 1H), 4.71-4.66 (m, 1H), 3.81 (dd, J=5.4, 14.2Hz, 1H), 3.72-3.29 (m, 5H), 2.27 (s, 3H), 2.21 (s, 3H), 1.07 (t, J=6.8Hz, 3H), 1.06 (t, J=6.8 Hz, 3H).

MS (m/e): 411 (M⁺), 365, 232, 103

Example 32(RS)-5-Bromo-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.74 (s, 1H), 7.48-7.15 (m, 4H), 7.10-6.88 (m, 4H),5.03 (d, J=7.4 Hz, 1H), 4.72-4.60 (m, 1H), 3.90-3.37 (m, 6H), 2.21 (s,3H), 1.07 (t, J=6.4 Hz, 6H).

EXAMPLES 33 TO 41

The following compounds were prepared in the same manner as in Example28, except for replacing p-tolyl isocyanate used as a reactant inExample 28 with various isocyanates.

Example 33(RS)-3-(N'-(4-Chlorophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

NMR (DMSO-d₆) δ: 8.97 (s, 1H), 7.40 (d, J=9.4 Hz, 2H), 7.29-6.96 (m,7H), 5.06 (d, J=7.3 Hz, 1H), 4.72-4.67 (m, 1H), 3.84 (dd, J=5.4, 14.1Hz, 1H), 3.70-3.41 (m, 5H), 1.13-1.03 (m, 6H).

MS (m/e): 419, 417 (M⁺), 374, 371, 153, 103

Example 34(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methoxyphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.37 (d, J=7.3 Hz, 1H), 7.26-7.01 (m, 6H), 6.76 (d, J=8.8Hz, 2H), 5.80 (d, J=7.8 Hz, 1H), 5.19 (d, J=7.8 Hz, 1H), 4.70-4.65 (m,1H), 3.91 (dd, J=5.4, 14.6 Hz, 1H), 3.74-3.43 (m, 5H), 3.70 (s, 3H),1.65-1.12 (m, 6H).

MS (m/e): 413 (M⁺), 367, 218, 103

Example 35(RS)-3-(N'-Cyclohexylureido)-1-(2,2-diethoxyethyl)indolin-2-one

NMR (CDCl₃) δ: 7.39 (d, J=7.8 Hz, 1H), 7.27 (dd, J=7.3, 7.8 Hz, 1H),7.08-7.01 (m, 2H), 5.18-5.05 (m, 3H), 4.71-4.65 (m, 1H), 3.92 (dd,J=5.4, 14.1 Hz, 1H), 3.80-3.42 (m, 6H), 2.02-1.88 (m, 2H), 1.78-1.51 (m,4H), 1.48-1.02 (m, 10H).

MS (m/e): 389 (M⁺), 343, 218, 103

Example 36(RS)-3-(N'-(2-Chlorophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

NMR (CDCl₃ -DMSO-d₆) δ: 8.25 (dd, J=1.5, 6.8 Hz, 1H), 8.05 (s, 1H), 7.66(d, J=7.3 Hz, 1H), 7.41-7.00 (m, 6H), 6.91 (dt, J=1.5, 7.8 Hz, 1H), 5.23(d, J=7.3 Hz, 1H), 4.75-4.69 (m, 1H), 3.95 (dd, J=5.4, 14.1 Hz, 1H),3.82-3.42 (m, 5H), 1.16 (t, J=7.3 Hz, 3H), 1.15 (t, J=6.8 Hz, 3H).

MS (m/e): 419, 417 (M⁺), 373, 371, 103

Example 37(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-fluorophenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.81 (s, 1H), 7.42-6.95 (m, 9H), 5.07 (d, J=7.8 Hz,1H), 4.70 (dd, J=3.4 Hz, 5.4 Hz, 1H), 3.85 (dd, J=5.4, 14.1 Hz, 1H),3.74-3.34 (m, 5H), 1.074 (t, J=6.8 Hz, 3H), 1.067 (t, J=6.8 Hz, 3H).

MS (m/e): 401 (M⁺), 355, 218, 202, 146, 103, 75

Example 38 (RS)-1-(2,2-Diethoxyethyl)-3-(N'-phenylureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.78 (s, 1H), 7.39-6.86 (m, 10H), 5.07 (d, J=7.3 Hz,1H), 4.70 (dd, J=4.9 Hz, 5.4 Hz, 1H), 3.84 (dd, J=5.4, 14.1 Hz, 1H),3.70-3.41 (m, 5H), 1.07 (t, J=6.8 Hz, 3H), 1.06 (t, J=6.8 Hz, 3H).

MS (m/e): 383 (M⁺), 337, 202, 174, 119, 103, 75

Example 39(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.65 (s, 1H), 7.40-7.00 (m, 6H), 6.79 (d, J=9.3 Hz, 1H),6.53 (dd, J=2.4, 8.3 Hz, 1H), 6.07 (d, J=7.8 Hz, 1H), 5.17 (d, J=7.3 Hz,1H), 4.69 (dd, J=5.4, 5.9 Hz, 1H), 3.92 (dd, J=5.4, 14.1 Hz, 1H),3.79-3.45 (m, 5H), 3.70 (s, 3H), 1.14 (t, J=7.3 Hz, 3H), 1.13 (t, J=7.3Hz, 3H).

MS (m/e): 413 (M⁺), 367, 218, 202, 174, 103, 75

Example 40 (RS)-1-(2,2-Diethoxyethyl)-3-(N'-ethylureido)indolin-2-one

NMR (CDCl₃) δ: 7.40-7.01 (m, 4H), 5.26-5.16 (m, 3H), 4.68 (dd, J=5.4,5.4 Hz, 1H), 3.91 (dd, J=5.4, 14.6 Hz, 1H), 3.77-3.65 (m, 3H), 3.56-3.45(m, 2H), 3.30-3.17 (m, 2H), 1.15 (t, J=7.3 Hz, 3H), 1.14 (t, J=6.8 Hz,3H), 1.13 (t, J=7.3 Hz, 3H).

MS (m/e): 335 (M⁺), 289, 218, 189, 146, 131, 117, 103, 75

Example 41(RS)-3-(N'-(4-Ethoxycarbonylphenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

NMR (CDCl₃) δ: 8.07 (s, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.41-7.06 (m, 6H),6.36 (br, 1H), 5.15 (d, J=6.8 Hz, 1H), 4.73 (dd, J=4.9, 4.9 Hz, 1H),4.31 (q, J=7.3 Hz, 2H), 3.99 (dd, J=4.9, 14.1 Hz, 1H), 3.86-3.48 (m,5H), 1.36 (t, J=7.3 Hz, 3H), 1.15 (t, J=6.8 Hz, 3H), 1.14 (t, J=6.8 Hz,3H).

REFERENCE EXAMPLE 22 3-(Benzyloxyimino)-7-methylindolin-2-one

To a suspension of 4.91 g of 7-methylisatin in 100 ml of ethanol wasadded a solution of 5.59 g of O-benzylhydroxylamine hydrochloride and3.29 g of sodium acetate in 40 ml of water at room temperature. Themixture was stirred at room temperature for 3 hours and concentrated.The concentrate was diluted with chloroform and washed with water. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.Recrystallization of the crude product from benzene yielded 5.40 g (68%)of the title compound.

Rf=0.46 (chloroform/methanol=10/1)

NMR (DMSO-d₆) δ: 10.81 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.43-7.34 (m,5H), 7.20 (d, J=7.8 Hz, 1H), 6.93 (t, J=7.8 Hz, 1H), 5.45 (s, 2H), 2.19(s, 3H).

MS (m/e): 266 (M⁺), 249, 131, 91

REFERENCE EXAMPLE 23(RS)-7-Methyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

A suspension of 1.30 g of 3-(benzyloxyimino)-7-methylindolin-2-one and50 mg of 5% Pd/C in 500 ml of methanol was stirred under a hydrogenatmosphere at room temperature for 2 days. The reaction mixture wasfiltered through Cerite, and the filtrate was concentrated. The residuewas dissolved in 20 ml of dichloromethane, and 0.67 g of p-tolylisocyanate was added thereto at 0° C. The mixture was stirred at thattemperature for 2 hours, followed by concentration. The concentrate waswashed with ethyl ether to yield 1.00 g (69%) of the title compound.

Rf=0.51 (hexane/ethyl acetate=2/1)

NMR (DMSO-d₆) δ: 10.36 (s, 1H), 8.60 (s, 1H), 7.31-6.79 (m, 8H), 4.96(d, J=7.8 Hz, 1H), 2.21 (s, 3H), 2.20 (s, 3H).

MS (m/e): 295 (M⁺), 188, 162, 107

Example 42(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methylphenyl)ureido)indolin-2-one

To a suspension of 5.0 g of isatin in 200 ml of ethanol was added asolution of 9.75 g of O-benzylhydroxylamine hydrochloride and 4.18 g ofsodium acetate in 50 ml of water at room temperature. The mixture wasstirred at room temperature for 3 hours and concentrated. Theconcentrate was diluted with ethyl acetate and then washed with water.The organic layer was dried over anhydrous sodium sulfate andconcentrated. Recrystallization of the crude product from ethanol gave6.06 g (71%) of 3-(benzyloxyimino)indolin-2-one as yellow crystals.

Rf=0.49 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 9.70-9.40 (br, 1H), 7.85 (d, J=7.4 Hz, 1H), 7.50-6.70 (m,3H), 7.34 (s, 5H), 5.46 (s, 2H).

To a suspension of 0.35 g of sodium hydride (60%) in 20 ml ofN,N-dimethylformamide was added dropwise a solution of 2.00 g of3-(benzyloxyimino)indolin-2-one in 20 ml of N,N-dimethylformamide at 0°C. in a nitrogen stream. After stirring the mixture at room temperaturefor 1 hour, 1.40 ml of bromoacetaldehyde diethyl acetal was addedthereto, and the mixture was stirred for 12 hours at 70° C. The reactionmixture was concentrated, and the residue was diluted with ethyl acetateand washed with an aqueous solution of sodium chloride. The organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresulting crude product was purified by silica gel column chromatography(chloroform/methanol=100/1) to give 2.20 g (76%) of3-(benzyloxyimino)-1-(2,2-diethoxyethyl)indolin-2-one.

Rf=0.27 (dichloromethane/methanol=100/1)

NMR (CDCl₃) δ: 8.00-7.80 (m, 1H), 7.60-6.80 (m, 3H), 7.38 (s, 5H), 5.51(s, 2H), 4.71 (t, J=5.4 Hz, 1H), 4.00-3.20 (m, 6H), 1.14 (t, J=7.2 Hz,6H).

A suspension of 2.20 g of3-(benzyloxyimino)-1-(2,2-diethoxyethyl)indolin-2-one and 100 mg of 5%Pd/C in 50 ml of methanol was stirred under a hydrogen atmosphere atroom temperature for 2 days. The reaction mixture was filtered throughCerite, and the filtrate was concentrated. The residue was dissolved in20 ml of dichloromethane, and 0.89 ml of m-tolyl isocyanate was addedthereto at 0° C. The mixture was stirred at room temperature for 2hours, followed by concentration. The concentrate was recrystallizedfrom ethyl ether to yield 1.13 g (47%) of the title compound.

Rf=0.14 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 8.69 (s, 1H), 8.29 (s, 1H), 7.29-6.94 (m, 7H), 6.72 (d,J=6.8 Hz, 1H), 5.05 (d, J=7.8 Hz, 1H), 4.70 (dd, J=4.4, 5.4 Hz, 1H),3.81 (dd, J=5.4, 14.1 Hz, 1H), 3.70-3.29 (m, 5H), 2.22 (s, 3H), 1.074(t, J=6.8 Hz, 3H), 1.067 (t, J=6.8 Hz, 3H).

Example 43(RS)-1-(2,2-Diethoxyethyl)-5-fluoro-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 42,except for using 5-fluoroisatin as a starting material in place ofisatin used in Example 42.

NMR (CDCl₃) δ: 7.20-6.82 (m, 8H), 6.10 (d, J=6.9 Hz, 1H), 5.09 (d, J=6.9Hz, 1H), 4,71-4.66 (m, 1H), 4.02-3.64 (m, 6H), 2.25 (s, 3H), 1.17-1.09(m, 6H).

Example 44(RS)-1-(2,2-Ethoxyethyl)-5-methoxy-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 42,except for using 5-methoxyisatin as a starting material in place ofisatin used in Example 42.

NMR (CDCl₃) δ: 7.46 (br, 1H), 7.17 (d, J=8.2 Hz, 2H), 7.11-6.93 (m, 4H),6.78 (dd, J=2.6, 8.2 Hz, 1H), 5.97 (d, J=6.9 Hz, 1H), 5.14 (d, J=6.9 Hz,1H), 4.69-4.64 (m, 1H), 3.90 (dd, J=5.3, 14.2 Hz, 1H), 3.76 (s, 3H),3.74-3.64 (m, 3H), 3.54-3.42 (m, 2H), 2.25 (s, 3H), 1.16-1.10 (m, 6H).

EXAMPLES 45 TO 52

The following compounds were prepared in the same manner as in Example42, except for replacing p-tolyl isocyanate used as a reactant inExample 42 with various isocyanate compounds.

Example 45(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(2-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 7.91 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.37-6.84 (m,8H), 5.12 (d, J=7.3 Hz, 1H), 4.70 (dd, J=5.4, 5.4 Hz, 1H), 3.84 (dd,J=5.4, 14.6 Hz, 1H), 3.70-3.26 (m, 5H), 2.20 (s, 3H), 1.07 (t, J=7.3 Hz,3H), 1.06 (t, J=7.3 Hz, 3H).

Example 46(RS)-3-(N'-(3-Chlorophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.03 (s, 1H), 7.63 (s, 1H), 7.30-6.89 (m, 8H), 5.06 (d,J=7.8 Hz, 1H), 4.70 (dd, J=3.4, 5.4 Hz, 1H), 3.86 (dd, J=5.4, 14.6 Hz,1H), 3.71-3.30 (m, 5H), 1.09 (t, J=7.3 Hz, 3H), 1.08 (t, J=7.3 Hz, 3H).

Example 47(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(2-methoxyphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 8.14 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.8Hz, 1H), 7.30-6.76 (m, 7H), 5.12 (d, J=7.8 Hz, 1H), 4.70 (dd, J=4.9, 5.4Hz, 1H), 3.85 (s, 3H), 3.88-3.29 (m, 6H), 1.08 (t, J=6.8 Hz, 3H), 1.07(t, J=6.8 Hz, 3H).

Example 48(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-nitrophenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.61 (s, 1H), 8.11 (d, J=9.3 Hz, 2H), 7.61 (d, J=9.3Hz, 2H), 7.34-6.97 (m, 5H), 5.01 (d, J=7.3 Hz, 1H), 4.70 (dd, J=2.9, 5.4Hz, 1H), 3.86 (dd, J=5.4, 14.1 Hz, 1H), 3.71-3.42 (m, 5H), 1.08 (t,J=7.3 Hz, 6H).

Example 49(RS)-3-(N'-(4-Cyanophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.36 (s, 1H), 7.70-7.53 (m, 5H), 7.30-7.21 (m, 2H),7.09-6.96 (m, 2H), 5.09 (d, 7.3 Hz, 1H), 4.70 (dd, J=3.4, 5.4 Hz, 1H),3.86 (dd, J=5.4, 14.1 Hz, 1H), 3.71-3.41 (m, 5H), 1.08 (t, J=7.3 Hz,3H), 1.07 (t, J=7.3 Hz, 3H).

Example 50(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-trifluoromethylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.04 (s, 1H), 7.55 (s, 1H), 7.39-7.03 (m, 7H), 6.62 (d,J=6.8 Hz, 1H), 5.06 (d, J=6.8 Hz, 1H), 4.73 (dd, J=4.9, 4.9 Hz, 1H),3.98-3.46 (m, 6H), 1.14 (t, J=6.8 Hz, 3H), 1.13 (t, J=6.8 Hz, 3H).

Example 51(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-fluorophenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.05 (s, 1H), 7.42-6.96 (m, 8H), 6.68 (dt, J=2.4, 8.3Hz, 1H), 5.07 (d, J=7.8 Hz, 1H), 4.70 (dd, J=4.9, 5.4 Hz, 1H), 3.85 (dd,J=5.4, 14.1 Hz, 1H), 3.70-3.30 (m, 5H), 1.08 (t, J=7.3 Hz, 3H), 1.06 (t,J=7.3 Hz, 3H).

Example 52(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-trifluoromethylphenyl)ureido)indolin-2-one

Rf=0.28 (n-hexane/ethyl acetate=1/1)

NMR (DMSO-d₆) δ: 9.26 (s, 1H), 7.61-6.97 (m, 9H), 5.09 (d, J=7.8 Hz,1H), 4.70 (dd, J=4.9, 5.4 Hz, 1H), 3.86 (dd, J=5.4, 14.1 Hz, 1H),3.74-3.42 (m, 5H), 1.07 (t, J=7.3 Hz, 6H).

Example 53(RS)-1,3-Bis(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one(53a) and(RS)-3-(Ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one(53b)

To a solution of 2.81 g of(RS)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 80 ml of dry dimethylsulfoxide was added 10 ml of a 1M solution of potassium t-butoxide indry dimethyl sulfoxide at room temperature under a nitrogen atmosphere.After stirring for 1 hour, 1.11 ml of ethyl bromoacetate was dropwiseadded thereto, followed by stirring at the same temperature for 1 hour.The reaction mixture was treated with an aqueous solution of sodiumchloride and extracted with ethyl ether. The ethyl ether layer was driedover anhydrous magnesium sulfate, and concentrated. The concentrate waspurified by silica gel column chromatography (chloroform/methanol=40/1)to give 0.68 g (15%) of(RS)-1,3-bis(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one:

Rf=0.57 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 8.97 (s, 1H), 7.24-6.94 (m, 9H), 4.59 (d, J=16.1 Hz,1H), 4.51 (d, J=16.1 Hz, 1H), 4.17-4.00 (m, 4H), 2.89 (d, J=15.1 Hz,1H), 2.53 (d, J=15.1 Hz, 1H), 2.18 (s, 3H), 1.22 (t, J=6.8 Hz, 3H), 1.11(t, J=7.3 Hz, 3H).

MS (m/e): 453 (M⁺), 408, 346, 320, 233, 107

and 1.64 g (45%) of(RS)-3-(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one:

Rf=0.22 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 10.39 (s, 1H), 8.79 (s, 1H), 7.24-6.77 (m, 9H), 3.99(q, J=6.8 Hz, 2H), 2.84 (d, J=14.6 Hz, 1H), 2.63 (d, J=14.6 Hz, 1H),2.18 (s, 3H), 1.06 (t, J=6.8 Hz, 3H).

MS (m/e): 367 (M⁺), 321, 206, 133, 107

Example 54(RS)-3-(N'-(4-Methylphenyl)ureido-1,3-bis(phenylcarbonylmethyl)indolin-2-one(54a) and(RS)-3-(N'-(4-Methylphenyl)ureido-3-(phenylcarbonylmethyl)indolin-2-one(54b)

The two title compounds were prepared in the same manner as in Example53, except for replacing ethyl bromoacetate used in Example 53 with2-bromoacetophenone.

(RS)-3-(N'-(4-Methylphenyl)ureido)-1,3-bis(phenylcarbonylmethyl)indolin-2-one:

Rf=0.73 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 9.01 (s, 1H), 8.14 (d, J=6.8 Hz, 2H), 7.85 (d, J=6.8Hz, 2H), 7.67-6.88 (m, 15H), 5.37 (s, 2H), 3.63 (d, J=15.1 Hz, 1H), 3.42(d, J=15.1 Hz, 1H), 2.19 (s, 3H).

MS (m/e): 517 (M⁺), 410, 367, 262, 150, 105

(RS)-3-(N'-(4-Methylphenyl)ureido)-3-(phenylcarbonylmethyl)indolin-2-one(54b):

Rf=0.33 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 10.41 (s, 1H), 8.81 (s, 1H), 7.88 (d, J=7.3 Hz, 2H),7.65-7.44 (m, 3H), 7.30-6.77 (m, 9H), 3.68 (d, J=16.5 Hz, 1H), 3.44 (d,J=16.5 Hz, 1H), 2.19 (S, 3H).

MS (m/e): 399 (M⁺), 381, 338, 266, 249, 107

Example 55(RS)-3-(Hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

A solution of 300 mg of potassium hydroxide (85%) in 2 ml of water wasadded to a solution of 0.35 g of(RS)-3-(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 10 ml of ethanol at room temperature, and the mixture was stirred for4 hours, followed by concentration. The concentrate was diluted withwater, and washed with chloroform. The aqueous layer was adjusted to pH3 by addition of 2N hydrochloric acid, and extracted with ethyl acetate.The organic layer was dried over sodium sulfate and concentrated. Theresulting crude product was recrystallized from isopropyl alcohol togive 0.088 g (27%) of the title compound.

Rf=0.16 (chloroform/methanol=2/1)

NMR (DMSO-d₆) δ: 12.70 (br, 1H), 10.36 (s, 1H), 8.88 (s, 1H), 7.26-6.75(m, 9H), 2.77 (d, J=16.1 Hz, 1H), 2.49 (d, J=16.1 Hz, 1H), 2.18 (s, 3H).

MS (m/e): 339 (M+), 321, 160, 133, 107

Example 56(RS)-1,3-Bis(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was obtained (yield: 75%) in the same manner as inExample 55, except for replacing(RS)-3-(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 55 with(RS)-1,3-bis(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one.

Rf=0.17 (chloroform/methanol=1/1)

NMR (DMSO-d₆) δ: 12.71 (br, 2H), 9.07 (s, 1H), 7.31-6.93 (m, 9H), 4.42(d, J=17.5 Hz, 1H), 4.37 (d, J=17.5 Hz, 1H), 2.82 (d, J=14.9 Hz, 1H),2.37 (d, J=14.9 Hz, 1H), 2.18 (s, 3H).

MS (m/e): 379 (M⁺ -18), 335, 133, 107

Example 57(RS)-3-(4-Methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.150 g of(RS)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneand 0.103 g of dicyclohexylcarbodiimide in 10 ml ofN,N-dimethylformamide were added successively 0.074 g of1-hydroxybenzotriazole and 0.052 g of p-toluidine. The resulting mixturewas stirred at room temperature for 18 hours, followed by concentration.The residue was diluted with ethyl acetate and washed successively withdilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate.The organic layer was dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by silica gel columnchromatography (chloroform/methanol=20/1) to obtain 0.083 g (44%) of thetitle compound as a white powder.

Rf=0.11 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 10.37 (s, 1H), 9.89 (s, 1H), 9.15 (s, 1H), 8.29 (s,1H), 7.51-6.80 (m, 12H), 2.75 (d, J=14.1 Hz, 1H), 2.50 (d, J=14.1 Hz,1H), 2.25 (s, 3H), 2.18 (s, 3H).

MS (m/e): 428 (M⁺), 410, 321, 295, 147, 133, 107

EXAMPLES 58 TO 59

The following compounds were prepared in the same manner as in Example57, except for starting with various amines in place of p-toluidine usedin Example 57.

Example 58(RS)-3-(N'-(4-Methylphenyl)ureido)-3-(N-(N'-methylpiperazinyl)carbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 9.12 (br, 1H), 7.50 (s, 1H), 7.38-7.15 (m, 2H), 7.15-6.70(m, 7H), 3.60 (br, 2H), 3.30-2.95 (m, 2H), 2.98 (d, J=14.5 Hz, 1H), 2.75(d, J=14.5 Hz, 1H), 2.57-1.80 (br, 7H), 2.22 (s, 3H).

Example 59(RS)-3-(N'-(4-Methylphenyl)ureido)-3-((N-piperidyl)carbonylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 10.31 (s, 1H), 9.11 (s, 1H), 7.45 (s, 1H), 7.40-7.05(m, 4H), 7.05-6.74 (m, 4H), 3.48 (br, 2H), 3.27-3.00 (br, 2H), 2.71 (d,J=15.1 Hz, 1H), 2.64 (d, J=15.1 Hz, 1H), 2.18 (s, 3H), 1.70-1.12 (br,6H).

REFERENCE EXAMPLE 24(RS)-3-(Ethoxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-one

To a solution of 0.72 g of(RS)-3-((4-methylbenzyl)carbonylamino)indolin-2-one in 20 ml of drydimethyl sulfoxide was added 3 ml of a 1M solution of potassiumt-butoxide in dry dimethyl sulfoxide at room temperature under anitrogen atmosphere, followed by stirring for 30 minutes. To the mixturewas added dropwise 0.37 ml of ethyl bromoacetate, followed by stirringat the same temperature for 30 minutes. The reaction mixture was treatedwith an aqueous solution of sodium chloride and extracted with ethylether. The ethyl ether layer was dried over anhydrous magnesium sulfateand concentrated. The residue was purified by silica gel columnchromatography (chloroform/methanol=40/1) to give 0.30 g (32%) of thetitle compound.

Rf=0.36 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 10.35 (s, 1H), 8.63 (s, 1H), 7.16-7.05 (m, 6H),6.88-6.71 (m, 2H), 3.82 (q, J=6.8 Hz, 2H), 3.40 (d, J=12.7 Hz, 1H), 3.32(d, J=12.7 Hz, 1H), 2.95 (d, J=14.6 Hz, 1H), 2.74 (d, J=14.6 Hz, 1H),2.25 (s, 3H), 0.96 (t, J=6.8 Hz, 3H).

MS (m/e): 366 (M⁺), 322, 233, 218, 146, 132, 105

REFERENCE EXAMPLE 25(RS)-1-Benzyl-3-ethoxycarbonylmethyl-3-(methylcarbonylamino)indolin-2-one

To a solution of 0.84 g of(RS)-1-benzyl-3-(methylcarbonylamino)indolin-2-one in 15 ml of drydimethyl sulfoxide was added 3 ml of a 1M solution of potassiumt-butoxide in dry dimethyl sulfoxide at room temperature under anitrogen atmosphere, followed by stirring for 10 minutes. To thesolution was added dropwise 1.11 ml of ethyl bromoacetate, followed bystirring at the same temperature for 30 minutes. The reaction mixturewas poured into an aqueous solution of sodium chloride and extractedwith ethyl ether. The ethyl ether layer was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography (chloroform/ethyl acetate=3/1) to give 0.83 g(76%) of the title compound as a colorless oil.

Rf=0.21 (chloroform/ethyl acetate=5/1)

NMR (CDCl₃) δ: 7.58 (s, 1H), 7.43-7.11 (m, 7H), 6.96 (t, J=7.3 Hz, 1H),6.66 (d, J=7.8 Hz, 1H), 5.02 (d, J=16.1 Hz, 1H), 4.92 (d, J=16.1 Hz,1H), 4.21 (q, J=7.3 Hz, 2H), 2.99 (d, J=15.1 Hz, 1H), 2.50 (d, J=15.1Hz, 1H), 2.02 (s, 3H), 1.25 (t, J=7.3 Hz, 3H).

MS (m/e): 366 (M⁺), 307, 278, 238, 91

Example 60(RS)-3-((4-Methylbenzyl)carbonylamino)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

To a solution of 0.29 g of(RS)-3-(ethoxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-onein 10 ml of ethanol was added 2 ml of an aqueous solution of 0.16 g ofpotassium hydroxide (85%) at room temperature, and the mixture wasstirred for 4 hours, followed by concentration. The concentrate wasdiluted with water, and washed with chloroform. The aqueous layer wasadjusted to pH 2 by addition of 2N hydrochloric acid and extracted withethyl acetate. The organic layer was dried over sodium sulfate andconcentrated to obtain(RS)-3-(hydroxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-one.

Rf=0.24 (chloroform/methanol=2/1)

NMR (DMSO-d₆) δ: 12.32 (br, 1H), 10.32 (s, 1H), 8.59 (s, 1H), 7.19-7.05(m, 6H), 6.88-6.71 (m, 2H), 3.40 (d, J=15.1 Hz, 1H), 3.28 (d, J=15.1 Hz,1H), 2.89 (d, J=15.1 Hz, 1H), 2.62 (d, J=15.1 Hz, 1H), 2.23 (s, 3H).

MS (m/e): 388 (M⁺), 294, 205, 146, 132, 105

The above obtained(RS)-3-(hydroxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-onewas dissolved in 20 ml of N,N-dimethylformamide, and 0.248 g ofdicyclohexylcarbodiimide, 0.184 g of 1-hydroxybenzotriazole, and 0.128 gof p-toluidine were successively added thereto. The resulting mixturewas stirred at room temperature for 12 hours, followed by concentration.The concentrate was diluted with ethyl acetate, washed successively withdilute hydrochloric acid and saturated aqueous sodiumhydrogen-carbonate. The organic layer was dried over anhydrous sodiumsulfate, and concentrated. The resulting crude product was purified bysilica gel column chromatography (chloroform/methanol=40/1) to afford0.273 g (81%) of the title compound as a white powder.

Rf=0.28 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 10.36 (s, 1H), 9.81 (s, 1H), 8.68 (s, 1H), 7.31 (d,J=8.3 Hz, 2H), 7.14-7.04 (m, 8H), 6.85-6.73 (m, 2H), 3.45 (d, J=15.2 Hz,1H), 3.35 (d, J=15.2 Hz, 1H), 2.86 (d, J=14.1 Hz, 1H), 2.58 (d, J=14.1Hz, 1H), 2.26 (s, 3H), 2.23 (s, 3H).

MS (m/e): 427 (M⁺), 322, 293, 279, 172, 149, 107

Example 61(RS)-1-Benzyl-3-methylcarbonylamino-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

The title compound was prepared in the same manner as in Example 60,except for starting with(RS)-1-benzyl-3-ethoxycarbonylmethyl-3-(methylcarbonylamino)indolin-2-onein place of(RS)-3-(ethoxycarbonylmethyl)-3-((4-methylbenzyl)carbonylamino)indolin-2-oneused in Example 60.

Rf=0.43 (chloroform/methanol 10/1)

NMR (CDCl₃) δ: 8.23 (s, 1H), 7.57 (s 1H), 7.42-7.12 (m, 11H), 6.95 (t,J=7.3 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 4.95 (s, 2H), 3.04 (d, J=14.1 Hz,1H), 2.33 (s, 3H), 2.25 (d, J=14.1 Hz, 1H), 1.96 (s, 3H).

MS (m/e): 427 (M⁺), 293, 262, 237, 107, 91

Example 62(RS)-1-Benzyl-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.404 g of(RS)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 20 ml of dry dimethyl sulfoxide was added 2.5 ml of a 1M solution ofsodium hydride in dry dimethyl sulfoxide at room temperature under anitrogen atmosphere. After stirring the mixture for 15 minutes, 0.19 mlof benzyl bromide was added thereto, followed by stirring at the sametemperature for 30 minutes. The reaction mixture was poured into anaqueous solution of sodium chloride and extracted with ethyl ether. Theethyl ether layer was dried over anhydrous magnesium sulfate andconcentrated to give(RS)-1-benzyl-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one.

Rf=0.41 (chloroform/methanol=2/1)

(RS)-1-Benzyl-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onewas dissolved in 15 ml of dry N,N-dimethylformamide, and 0.080 g of1-hydroxybenzotriazole, 0.1 ml of diisopropylethylamine, 0.111 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.065 gof p-toluidine were successively added to the solution. The mixture wasstirred for 6 hours and concentrated. The concentrate was diluted withethyl acetate and washed successively with dilute hydrochloric acid anda saturated aqueous solution of sodium hydrogen-carbonate. The organiclayer was dried over anhydrous sodium sulfate and concentrated. Thecrude product was purified by silica gel column chromatography(chloroform/ethyl acetate=4/1) to give 0.350 g (57%) of the titlecompound as a white powder.

NMR (DMSO-d₆) δ: 9.93 (s, 1H), 9.16 (s, 1H), 7.51 (s, 1H), 7.53-6.70 (m,17H), 4.94 (s, 2H), 2.90 (d, J=14.8 Hz, 1H), 2.57 (d, J=14.8 Hz, 1H),2.26 (s, 3H), 2.19 (s, 3H).

EXAMPLES 63 TO 70

The following compounds were prepared in the same manner as in Example62, except for starting with various alkyl halides in place of benzylbromide used in Example 62.

Example 63(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-(phenylcarbonylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 10.18 (s, 1H), 9.28 (s, 1H), 8.19 (s, 1H), 7.85-6.80(m, 17H), 5.57 (d, J=8.6 Hz, 1H), 5.36 (d, J=8.6 Hz, 1H), 2.90 (d,J=15.4 Hz, 1H), 2.65 (d, J=15.4 Hz, 1H), 2.82 (s, 3H), 2.20 (s, 3H).

Example 64(RS)-1-(Ethoxycarbonylmethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 10.08 (s, 1H), 9.24 (s, 1H), 7.74 (s, 1H), 7.46 (d,J=7.2 Hz, 2H), 7.40-6.88 (m, 10H), 4.78-4.46 (m, 2H), 4.16 (q, J=7.2 Hz,2H), 2.90 (d, J=14.8 Hz, 1H), 2.57 (d, J=14.8 Hz, 1H), 2.26 (s, 3H),2.18 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).

Example 65(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-(2-pyridylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.96 (s, 1H), 9.21 (s, 1H), 8.30 (s, 1H), 7.80-6.70 (m,16H), 5.00 (s, 2H), 2.86 (d, J=14.3 Hz, 1H), 2.59 (d, J=14.3 Hz, 1H),2.50 (s, 3H), 2.25 (s, 3H).

Example 66(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-(2-phenylethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.90 (s, 1H), 9.13 (s, 1H), 7.56 (s, 1H), 7.45-6.85 (m,17H), 4.98-4.77 (br, 2H), 2.99-2.80 (br, 2H), 2.81 (d, J=14.2 Hz, 1H),2.48 (d, J=14.2 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H).

Example 67(RS)-1-Methyl-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.88 (s, 1H), 9.12 (s, 1H), 7.54 (s, 1H), 7.39 (d,J=8.2 Hz, 2H), 7.31-6.95 (m, 10H), 3.17 (s, 3H), 2.80 (d, J=14.6 Hz,1H), 2.52 (d, J=14.6 Hz, 1H), 2.25 (s, 3H), 2.18 (s, 3H).

Example 68(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-(4-pyridylmethyl)indolin-2-one

NMR (DMSO-d₆)δ: 9.92 (s, 1H), 9.18 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.65(s, 1H), 7.50 (d, J=5.8 Hz, 2H), 7.40 (d, J=9.8 Hz, 2H), 7.28-6.86 (m,9H), 6.75 (d, J=7.2 Hz, 1H), 5.03 (d, J=16.6 Hz, 1H), 4.93 (d, J=16.6Hz, 1H), 2.90 (d, J=14.6 Hz, 1H), 2.63 (d, J=14.6 Hz, 1H), 2.26 (s, 3H),2.20 (s, 3H).

Example 69(RS)-1-(Methoxymethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.90 (s, 1H), 9.14 (s, 1H), 7.61 (s, 1H), 7.39 (d,J=7.8 Hz, 2H), 7.45-6.86 (m, 10H), 5.11 (s, 2H), 3.34 (s, 3H), 2.84 (d,J=14.0 Hz, 1H), 2.56 (d, J=14.0 Hz, 1H), 2.25 (s, 3H), 2.17 (s, 3H).

Example 70(RS)-3-((4-Methylphenyl)aminocarbonylmethyl))-3-(N'-(4-methylphenyl)ureido)-1-(2,2-di-n-propylethyl)indolin-2-one

NMR (CDCl₃) δ: 8.62 (s, 1H), 7.40-6.78 (m, 14H), 3.71 (dd, J=7.4, 13.7Hz, 1H), 3.52 (dd, J=6.9, 13.7 Hz, 1H), 2.97 (d, J=14.3 Hz, 1H), 2.62(d, J=14.3 Hz, 1H), 2.29 (s, 3H), 2.19 (s, 3H), 1.93 (br, 1H), 1.50-1.10(br, 8H), 0.98-0.70 (br, 6H).

Example 71(RS)-1-(2,2-Diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.397 g of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in4 ml of dry dimethyl sulfoxide was added 1 ml of a 1M solution ofpotassium t-butoxide in dry dimethyl sulfoxide at room temperature undera nitrogen atmosphere, followed by stirring for 30 minutes. To themixture was added dropwise a solution of 0.228 g ofN-p-tolyl-2-bromoacetamide in 2 ml of dry dimethyl sulfoxide, followedby stirring at the same temperature for 30 minutes. The reaction mixturewas poured into an aqueous solution of sodium chloride and extractedwith ethyl ether. The ethyl ether layer was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=2/1) to give 0.35 g(65%) of the title compound.

Rf=0.21 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 8.33 (s, 1H), 7.33-6.91 (m, 14H), 4.77 (dd, J=4.4, 5.6Hz, 1H), 4.03 (dd, J=5.6, 14.1 Hz, 1H), 3.82-3.48 (m, 5H), 2.97 (d,J=14.6 Hz, 1H), 2.57 (d, J=14.6 Hz, 1H), 2.30 (s, 3H), 2.22 (s, 3H),1.16 (t, J=6.8 Hz, 3H), 1.11 (t, J=6.8 Hz, 3H).

MS (m/e): 544 (M⁺), 498, 437, 365, 103, 75

Example 72(RS)-7-Methyl-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared (yield: 30%) in the same manner as inExample 71, except for starting with7-methyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one in place of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 71.

Rf=0.21 (chloroform/methanol 20/1)

NMR (CDCl₃) δ: 9.10 (br, 1H), 8.61 (br, 1H), 7.42 (br, 1H), 7.26-6.73(m, 12H), 3.06 (d, J=14.5 Hz, 1H), 2.56 (d, J=14.5 Hz, 1H), 2.24 (s,3H), 2.19 (s, 3H), 2.03 (s, 3H).

MS (m/e): 442 (M⁺), 424, 381, 335, 161, 107

Example 73(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-phenylindolin-2-one

The title compound was prepared (yield: 57%) in the same manner as inExample 71, except for starting with3-(N'-(4-methylphenyl)ureido)-1-phenylindolin-2-one in place of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 71.

Rf=0.40 (chloroform/methanol=20/1)

NMR (DMSO-d₆) δ: 9.97 (s, 1H), 9.12 (s, 1H), 7.63-6.95 (m, 17H), 6.71(d, J=7.8 Hz, 1H), 2.95 (d, J=14.1 Hz, 1H), 2.75 (d, J=14.1 Hz, 1H),2.25 (s, 3H), 2.19 (s, 3H).

MS (m/e): 504 (M⁺), 397, 365, 224, 132, 107

EXAMPLES 74 TO 77

The following compounds were prepared in the same manner as in Example71, except for starting with(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one,used in Example 71, having a varied substituent at the 5-positionthereof.

Example 74(RS)-1-(2,2-Diethoxyethyl)-5-methyl-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.25 (s, 1H), 7.32 (d, J=8.3 Hz, 2H), 7.11-6.93 (m, 10H),6.84 (s, 1H), 4.78 (dd, J=4.4, 5.9 Hz, 1H), 3.99 (dd, J=5.9, 14.6 Hz,1H), 3.81-3.54 (m, 5H), 2.94 (d, J=14.6 Hz, 1H), 2.54 (d, J=14.6 Hz,1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 1.17 (t, J=6.8 Hz, 3H),1.12 (t, J=6.8 Hz, 3H).

MS (m/e): 558 (M⁺), 512, 451, 406, 379, 306, 103

Example 75(RS)-1-(2,2-Diethoxyethyl)-5-fluoro-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.61 (s, 1H), 7.35-6.86 (m, 13H), 4.72 (dd, J=4.5, 5.4Hz, 1H), 3.96 (dd, J=5.4, 14.6 Hz, 1H), 3.74-3.44 (m, 5H), 2.95 (d,J=14.6 Hz, 1H), 2.65 (d, J=14.6 Hz, 1H), 2.27 (s, 3H), 2.19 (s, 3H),1.12 (t, J=6.8 Hz, 3H), 1.09 (t, J=6.8 Hz, 3H).

Example 76(RS)-1-(2,2-Diethoxyethyl)-5-methoxy-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

Rf=0.20 (n-hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 8.35 (s, 1H), 7.34-6.75 (m, 13H), 4.76 (dd, J=4.3, 6.1Hz, 1H), 3.99 (dd, J=6.1, 14.5 Hz, 1H), 3.79-3.48 (m, 5H), 3.67 (s, 3H),2.97 (d, J=14.8 Hz, 1H), 2.61 (d, J=14.8 Hz, 1H), 2.29 (s, 3H), 2.22 (s,3H), 1.16 (t, J=6.9 Hz, 3H), 1.12 (t, J=6.9 Hz, 3H).

Example 77(RS)-5-Bromo-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.23 (s, 1H), 7.45-6.85 (m, 13H), 4.73 (dd, J=3.9, 5.9Hz, 1H), 3.98 (dd, J=5.9 Hz, 14.8 Hz, 1H), 3.83-3.40 (m, 5H), 2.94 (d,J=14.6 Hz, 1H), 2.56 (d, J=14.6 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H),1.15 (t, J=6.8 Hz, 3H), 1.11 (t, J=7.0 Hz, 3H).

EXAMPLES 78 TO 95

The following compounds were prepared in the same manner as in Example71, except for starting with(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one,used in Example 71, with its (4-methylphenyl)ureido moiety replaced withvarious substituted ureides.

Example 78(RS)-3-(N'-(4-Chlorophenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

Rf=0.33 (n-hexane/ethyl acetate=1/1)

NMR (CDCl₃) δ: 8.34 (s, 1H), 7.54 (s, 1H), 7.31-7.24 (m, 4H), 7.12-6.97(m, 9H), 4.78 (dd, J=4.4, 5.8 Hz, 1H), 4.03 (dd, J=5.8, 14.6 Hz, 1H),3.84-3.48 (m, 5H), 3.03 (d, J=14.6 Hz, 1H), 2.65 (d, J=14.6 Hz, 1H),2.28 (s, 3H), 1.19-1.07 (m, 6H).

Example 79(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

Rf=0.23 (n-hexane/ethyl acetate=1/1)

NMR (CDCl₃) δ: 8.33 (s, 1H), 7.33-6.95 (m, 12H), 6.67 (d, J=8.8 Hz, 2H),4.76 (dd, J=4.5, 5.9 Hz, 1H), 4.04 (dd, J=5.9, 14.1 Hz, 1H), 3.79-3.48(m, 5H), 3.70 (s, 3H), 2.95 (d, J=14.6 Hz, 1H), 2.56 (d, J=14.6 Hz, 1H),2.29 (s, 3H), 1.15 (t, J=6.9 Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

MS (m/e): 560 (M⁺), 514, 365, 217, 103

Example 80(RS)-1-(2,2-Diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-cyclohexylureido)indolin-2-one

Rf=0.25 (n-hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 8.14 (s, 1H), 7.38-6.93 (m, 9H), 6.80 (s, 1H), 4.80-4.75(m, 1H), 4.12 (dd, J=5.8, 14.6 Hz, 1H), 3.78-3.34 (m, 6H), 2.94 (d,J=14.6 Hz, 1H), 2.45 (d, J=14.6 Hz, 1H), 2.31 (s, 3H), 1.95-1.48 (m,6H), 1.38-0.92 (m, 10H).

MS (m/e): 536 (M⁺), 490, 462, 391, 103

Example 81(RS)-1-(2,2-Diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(3-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.39 (s, 1H), 7.34-6.97 (m, 13H), 6.75 (d, J=6.8 Hz, 1H),4.79 (dd, J=4.4, 5.9 Hz, 1H), 4.01 (dd, J=5.9, 14.4 Hz, 1H), 3.84-3.46(m, 5H), 2.98 (d, J=14.6 Hz, 1H), 2.59 (d, J=14.6 Hz, 1H), 2.30 (s, 3H),2.19 (s, 3H), 1.16 (t, J=6.8 Hz, 3H), 1.11 (t, J=6.8 Hz, 3H).

MS (m/e): 544 (M⁺), 498, 470, 437, 365, 292, 157, 103, 75

Example 82(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-fluorophenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.27 (s, 1H), 7.62 (s, 1H), 7.40-6.86 (m, 13H), 4.71(dd, J=4.6, 5.6 Hz, 1H), 3.86 (dd, J=5.6, 14.2 Hz, 1H), 3.70-3.35 (m,5H), 2.84 (d, J=15.2 Hz, 1H), 2.50 (d, J=15.2 Hz, 1H), 2.24 (s, 3H),1.11 (t, J=6.4 Hz, 3H), 1.07 (t, J=6.4 Hz, 3H).

MS (m/e): 548 (M⁺), 502, 365, 292, 158, 103, 75

Example 83(RS)-3-(N'-(2-Chlorophenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.85 (s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.83 (d,J=7.3 Hz, 1H), 7.38-6.88 (m, 11H), 4.70 (dd, J=4.9, 5.4 Hz, 1H), 3.84(dd, J=5.4, 13.7 Hz, 1H), 3.70-3.37 (m, 5H), 2.97 (d, J=14.6 Hz, 1H),2.61 (d, J=14.6 Hz, 1H), 2.23 (s, 3H), 1.07 (t, J=7.3 Hz, 6H).

MS (m/e): 564 (M⁺), 490, 365, 292, 173, 103, 75

Example 84(RS)-1-(2,2-Diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-phenylureido)indolin-2-one

NMR (CDCl₃) δ: 8.58 (s, 1H), 7.46 (s, 1H), 7.31-6.84 (m, 14H), 4.77 (dd,J=3.9, 5.9 Hz, 1H), 4.00 (dd, J=5.9, 14.1 Hz, 1H), 3.82-3.46 (m, 5H),2.99 (d, J=14.6 Hz, 1H), 2.67 (d, J=14.6 Hz, 1H), 2.27 (s, 3H), 1.13 (t,J=7.3 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).

MS (m/e): 530 (M⁺), 365, 292, 217, 158, 103, 75

Example 85(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.24 (s, 1H), 7.35-6.91 (m, 12H), 6.73 (d, J=7.3 Hz, 1H),6.50 (dd, J=2.4, 7.8 Hz, 1H), 4.79 (dd, J=3.9, 6.3 Hz, 1H), 3.98 (dd,J=6.3, 14.1 Hz, 1H), 3.86-3.52 (m, 5H), 3.67 (s, 3H), 2.98 (d, J=14.6Hz, 1H), 2.54 (d, J=14.6 Hz, 1H), 2.30 (s, 3H), 1.18 (t, J=6.8 Hz, 3H),1.10 (t, J=6.8 Hz, 3H).

MS (m/e): 560 (M⁺), 365, 350, 292, 217, 149, 103, 75

Example 86(RS)-1-(2,2-Diethoxyethyl)-3-(N'-ethylureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 7.97 (s, 1H), 7.37-6.88 (m, 9H), 4.79 (dd, J=3.9, 6.3 Hz,1H), 4.57 (br, 1H), 4.09 (dd, J=6.3, 14.6 Hz, 1H), 3.74-3.52 (m, 5H),3.11-3.05 (m, 2H), 2.94 (d, J=14.6 Hz, 1H), 2.44 (d, J=14.6 Hz, 1H),2.32 (s, 3H), 1.18 (t, J=7.3 Hz, 3H), 1.14 (t, J=6.8 Hz, 3H), 1.02 (t,J=7.3 Hz, 3H).

MS (m/e): 482 (M⁺), 416, 408, 216, 103, 75

Example 87(RS)-3-(N'-(4-Ethoxycarbonylphenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.16 (br, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.49-6.97 (m,12H), 4.81 (dd, J=4.9, 6.3 Hz, 1H), 4.30 (q, J=7.3 Hz, 2H), 4.02 (dd,J=6.3, 15.1 Hz, 1H), 3.89-3.57 (m, 5H), 3.02 (d, J=14.6 Hz, 1H), 2.57(d, J=14.6 Hz, 1H), 2.30 (s, 3H), 1.34 (t, J=7.3 Hz, 3H), 1.19 (t, J=6.8Hz, 3H), 1.12 (t, J=7.3 Hz, 3H).

MS (m/e): 602 (M⁺), 365, 146, 120, 103, 75

Example 88(RS)-1-(2,2-Diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(2-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.86 (s,1H), 8.28 (s, 1H), 7.80 (s, 1H), 7.52 (d, J=8.3Hz, 1H), 7.39-6.79 (m, 11H), 4.71 (dd, J=4.9, 5.4 Hz, 1H), 3.85 (dd,J=5.4, 14.1 Hz, 1H), 3.70-3.37 (m, 5H), 2.93 (d, J=14.6 Hz, 1H), 2.55(d, J=14.6 Hz, 1H), 2.25 (s, 3H), 2.17 (s, 3H), 1.10 (t, J=6.8 Hz, 3H),1.07 (t, J=6.8 Hz, 3H).

Example 89(RS)-3-(N'-(3-Chlorophenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.97 (s, 1H), 9.49 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H),7.41 (d, J=8.3 Hz, 2H), 7.24-6.89 (m, 9H), 4.75 (dd, J=4.3, 5.9 Hz, 1H),3.86 (dd, J=5.9, 14.2 Hz, 1H), 3.76-3.51 (m, 5H), 2.84 (d, J=15.2 Hz,1H), 2.09 (d, J=15.2 Hz, 1H), 2.26 (s, 3H), 1.14 (t, J=6.8 Hz, 3H), 1.08(t, J=6.8 Hz, 3H).

Example 90(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(2-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (DMSO-d₆) δ: 9.80 (br, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.79 (d,J=8.3 Hz, 1H), 7.35-6.71 (m, 11H), 4.70 (dd, J=5.0, 5.0 Hz, 1H),3.92-3.42 (m, 6H), 3.84 (s, 3H), 2.94 (d, J=14.4 Hz, 1H), 2.60 (d,J=14.4 Hz, 1H), 2.23 (s, 3H), 1.08 (t, J=7.3 Hz, 6H).

MS (m/e): 560 (M⁺), 514, 392, 365, 173, 158, 130, 103, 75

Example 91(RS)-1-(2,2-Diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-nitrophenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 10.03 (d, J=10.2 Hz, 2H), 8.04 (t, J=9.3 Hz, 3H),7.53-6.89 (m, 10H), 4.74 (dd, J=5.3, 5.9 Hz, 1H), 3.89 (dd, J=5.9, 14.2Hz, 1H), 3.72-3.50 (m, 5H), 2.86 (d, J=15.1 Hz, 1H), 2.51 (d, J=15.1 Hz,1H), 2.26 (s, 3H), 1.13 (t, J=6.8 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H).

Example 92(RS)-3-(N'-(4-Cyanophenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.05 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.37-6.98 (m,12H), 4.82 (dd, J=3.9, 6.3 Hz, 1H), 4.07 (dd, J=6.3, 15.2 Hz, 1H),3.87-3.54 (m, 5H), 3.09 (d, J=14.6 Hz, 1H), 2.58 (d, J=14.6 Hz, 1H),2.30 (s, 3H), 1.20 (t, J=7.3 Hz, 3H), 1.14 (t, J=7.3 Hz, 3H).

Example 93(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-trifluoromethylphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.32 (s, 1H), 7.62 (d, J=4.4 Hz, 2H), 7.43 (s, 1H),7.34-6.97 (m, 11H), 4.81 (dd, J=3.9, 5.9 Hz, 1H), 3.96-3.57 (m, 6H),3.07 (d, J=14.6 Hz, 1H), 2.62 (d, J=14.6 Hz, 1H), 2.29 (s, 3H), 1.19 (t,J=6.8 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H).

Example 94(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-fluorophenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.46 (s, 1H), 7.68 (s, 1H), 7.35-6.93 (m, 11H), 6.79 (d,J=7.8 Hz, 1H), 6.55 (split-t, J=8.8 Hz, 1H), 4.79 (dd, J=3.9, 5.9 Hz,1H), 3.98 (dd, J=5.9, 14.4 Hz, 1H), 3.88-3.49 (m, 5H), 3.04 (d, J=14.6Hz, 1H), 2.66 (d, J=14.6 Hz, 1H), 2.28 (s, 3H), 1.16 (t, J=7.3 Hz, 3H),1.11 (t, J=7.3 Hz, 3H).

Example 95(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-trifluoromethylphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

Rf=0.43 (n-hexane/ethyl acetate=1/1)

NMR (DMSO-d₆) δ: 9.99 (s, 1H), 9.71 (s, 1H), 7.84 (s, 1H), 7.48-6.89 (m,12H), 4.74 (dd, J=3.2, 5.8 Hz, 1H), 3.88 (dd, J=5.8, 13.6 Hz, 1H),3.72-3.51 (m, 5H), 2.86 (d, J=13.7 Hz, 1H), 2.51 (d, J=13.7 Hz, 1H),2.26 (s, 3H), 1.13 (t, J=7.3 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H).

Example 96(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-(2,2-dipropoxyethyl)indolin-2-one

To a solution of 0.411 g of(RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 50 ml of n-propanol was added 10 mg of p-toluenesulfonic acid, andthe mixture was heated under reflux for 2 hours. The reaction mixturewas concentrated, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1) to give 0.394 g (91%) of thetitle compound.

Rf=0.64 (hexane/ethyl acetate=1/1)

NMR (CDCl₃) δ: 8.55 (s, 1H), 7.35-6.80 (m, 14H), 4.74 (dd, J=4.4, 5.4Hz, 1H), 3.99 (dd, J=5.4, 14.6 Hz, 1H), 3.75 (dd, J=4.4, 14.6 Hz, 1H),3.68-3.32 (m, 4H), 2.95 (d, J=14.6 Hz, 1H), 2.62 (d, J=14.6 Hz, 1H),2.29 (s, 3H), 2.20 (s, 3H), 1.62-1.38 (m, 4H), 0.91-0.70 (m, 6H).

Example 97(RS)-1-(Formylmethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 4.32 g of(RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 50 ml of acetone was added 5 ml of 2N hydrochloric acid, and themixture was stirred at room temperature for 2 hours. The reactionmixture was poured into water, and the thus formed precipitate wascollected by filtration and washed with ethyl ether to obtain 2.94 g(79%) of the title compound.

NMR (DMSO-d₆) δ: 10.03 (s, 1H), 9.66 (s, 1H), 7.70 (s, 1H), 7.43 (d,J=8.2 Hz, 2H), 7.28-6.81 (m, 11H), 4.76 (d, J=18.0 Hz, 1H), 4.58 (d,J=18.0 Hz, 1H), 2.87 (d, J=14.8 Hz, 1H), 2.58 (d, J=14.6 Hz), 2.26 (s,3H), 2.18 (s, 3H).

Example 98(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-((2,5-dioxacyclopentyl)methyl)indolin-2-one

To a solution of 0.294 g of(RS)-1-(formylmethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 50 ml of toluene were added 0.5 ml of ethylene glycol and 10 mg ofp-toluenesulfonic acid. The mixture was heated under reflux for 6 hourswhile azeotropically removing produced water together with toluene. Thereaction mixture was washed with saturated aqueous sodiumhydrogencarbonate. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1) to give 0.220 g (68%) of thetitle compound.

NMR (DMSO-d₆) δ: 9.94 (s, 1H), 9.15 (s, 1H), 7.62 (s, 1H), 7.41 (d,J=8.2 Hz, 2H), 7.27-7.01 (m, 7H), 6.99-6.85 (m, 3H), 5.15-5.03 (m, 1H),4.05-3.63 (m, 6H), 2.83 (d, J=14.3 Hz, 1H), 2.47 (d, J=14.3 Hz, 1H),2.25 (s, 3H), 2.17 (s, 3H).

EXAMPLES 99 TO 101

The following compounds were prepared in the same manner as in Example98, except for replacing ethylene glycol used in Example 98 with variousalcohols.

Example 99(RS)-1-(2,2-Dibenzyloxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.90 (s, 1H), 9.11 (s, 1H), 7.60 (s, 1H), 7.45-6.85 (m,22H), 5.03 (dd, J=5.1, 6.8 Hz, 1H), 4.71 (d, J=11.7 Hz, 2H), 4.61 (d,J=11.7 Hz, 2H), 4.10-3.83 (m, 2H), 2.84 (d, J=14.8 Hz, 1H), 2.51 (d,J=14.8 Hz, 1H), 2.25 (s, 3H), 2.17 (s, 3H).

Example 100(RS)-1-(2,2-Dimethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.96 (s, 1H), 9.15 (s, 1H), 7.63 (s, 1H), 7.41 (d,J=8.2 Hz, 2H), 7.30-7.00 (m, 7H), 7.00-6.80 (m, 3H), 4.63 (dd, J=4.3,5.9 Hz, 1H), 3.91 (dd, J=5.9 Hz, 14.3 Hz, 1H), 3.69 (dd, J=4.3 Hz, 14.3Hz, 1H), 3.36 (s, 3H), 3.34 (s, 3H), 2.86 (d, J=14.3 Hz, 1H).

Example 101(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-((2.6-dioxa-3,5-dimethylcyclohexyl)methyl)indolin-2-one

NMR (CDCl₃) δ: 8.46 (s, 1H), 7.33-6.80 (m, 14H), 4.83 (dd, J=4.9, 4.9Hz, 1H), 4.12 (dd, J=4.9, 14.3 Hz, 1H), 3.78 (dd, J=4.9, 14.3 Hz, 1H),3.62 (br, 2H), 2.99 (d, J=14.6 Hz, 1H), 2.68 (d, J=14.6 Hz, 1H), 2.26(s, 3H), 2.19 (s, 3H), 1.50-0.95 (m, 8H).

Example 102(RS)-1-(2-Methylamino)ethyl-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.439 of(RS)-1-(formylmethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 15 ml of methanol was added 1 ml of a 40% aqueous solution ofmethylamine at room temperature. After adjusting the mixture to pH 7with trifluoroacetic acid, 0.30 g of sodium cyanoborohydride was addedthereto. The resulting mixture was stirred at room temperature for 1 dayand then concentrated. The concentrate was diluted with ethyl acetateand washed with an aqueous solution of sodium chloride. The organiclayer was dried over anhydrous sodium sulfate and concentrated. Thecrude product was purified by silica gel column chromatography(hexane/ethyl acetate=1/1) to afford 0.39 g (90%) of the title compound.

NMR (CDCl₃, for hydrochloride) δ: 9.10-8.75 (br, 1H), 7.95-7.50 (br,2H), 7.30-6.65 (m, 12H), 4.15-3.70 (br, 2H), 3.10-2.38 (br, 7H), 2.24(brs, 3H), 2.16 (brs, 3H).

Example 103(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-(2-(1-piperidyl)ethyl)indolin-2-one

The title compound was prepared (yield: 63%) in the same manner as inExample 102, except for replacing methylamine used in Example 102 withpiperidine.

NMR (CDCl₃) δ: 9.10 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.40-6.70 (m,12H), 4.10 (br, 2H), 3.10 (br, 8H), 2.23 (br, 3H), 2.20 (br, 3H).

Example 104(RS)-1-(2-Dimethylaminoethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 102,except for replacing methylamine used in Example 102 with dimethylamine.

NMR (DMSO-d₆) δ: 9.92 (s, 1H), 9.13 (s, 1H), 7.57 (s, 1H), 7.40 (d,J=8.4 Hz, 2H), 7.30-6.86 (m, 10H), 3.99-3.58 (m, 2H), 3.60-3.10 (m, 1H),2.82 (d, J=14.6 Hz, 1H), 2.70-2.35 (m, 2H), 2.28 (s, 6H), 2.25 (s, 3H),2.18 (s, 3H).

Example 105(RS)-3-((4-Methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)-1-(2,2-bis(methylthio)ethyl)indolin-2-one

Excess methyl mercaptan was bubbled through a solution of 0.538 g of(RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 30 ml of dichloromethane at -10° C., and 0.30 ml of boron trifluorideethyl etherate was added thereto, followed by stirring at roomtemperature for 1 hour. The reaction mixture was diluted withdichloromethane and washed successively with a 1N sodium hydroxideaqueous solution and water. The organic layer was dried over anhydroussodium sulfate and concentrated. The residue was washed withhexane/ethyl acetate=1/1 to give 0.495 g (91%) of the title compound.

Rf=0.48 (hexane/ethyl acetate=1/1)

NMR (DMSO-d₆) δ: 10.02 (s, 1H), 9.19 (s, 1H), 7.65 (s, 1H), 7.52-6.83(m, 12H), 4.30-3.94 (m, 2H), 3.85 (dd, J=6.4, 14.2 Hz, 1H), 2.86 (d,J=14.2 Hz, 1H), 2.54 (d, J=14.2 Hz, 1H), 2.25 (s, 3H), 2.20 (s, 3H),2.17 (s, 3H), 2.13 (s, 3H).

Example 106(RS)-1-(2,2-Bis(ethylthio)ethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.512 g of(RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 30 ml of dichloromethane were added successively 0.8 ml of ethylmercaptan and 0.30 ml of boron trifluoride ethyl etherate at roomtemperature, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was washed with a 1N sodium hydroxide aqueoussolution, and the organic layer was dried over anhydrous sodium sulfateand concentrated. The residue was washed with hexane/ethyl acetate=1/1to give 0.542 g (100%) of the title compound.

Rf=0.62 (n-hexane/ethyl acetate=1/1)

NMR (DMSO-d₆) δ: 10.00 (s, 1H), 9.17 (s, 1H), 7.64 (s, 1H), 7.43 (d,J=8.2 Hz, 2H), 7.30-6.78 (m, 10H), 4.38-4.26 (m, 1H), 4.14-3.79 (m, 2H),2.86 (d, J=14.8 Hz, 1H), 2.75 (q, J=7.3 Hz, 2H), 2.69 (q, J=7.3 Hz, 2H),2.38 (d, J=14.8 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 1.23 (t, J=7.3 Hz,3H), 1.17 (t, J=7.3 Hz, 3H).

Example 107 (RS)-3- (Ethoxycarbonylmethyl)-1-(2,2-diethoxyethyl )-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 7.50 g of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in100 ml of dry dimethyl sulfoxide was added 20 ml of a 1M solution ofpotassium t-butoxide in dry dimethyl sulfoxide at room temperature undera nitrogen atmosphere, followed by stirring for 30 minutes. To themixture was added dropwise a solution of 2.30 ml of ethyl bromoacetatein 20 ml of dry dimethyl sulfoxide, followed by stirring at the sametemperature for 30 minutes. A sodium chloride aqueous solution was addedthereto, and the mixture was extracted with ethyl ether. The ethyl etherlayer was dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=3/1) to afford 8.21 g (90%) of the title compound.

NMR (CDCl₃) δ: 7.34-7.24 (m, 2H), 7.19-6.95 (m, 7H), 6.76 (s, 1H), 4.76(dd, J=4.6, 5.9 Hz, 1H), 4.16-3.95 (m, 3H), 3.89-3.50 (m, 5H), 2.93 (d,J=15.4 Hz, 1H), 2.59 (d, J=15.4 Hz, 1H), 2.26 (s, 3H), 1.23-1.10 (m,9H).

Example 108(RS)-1-(2,2-Diethoxyethyl)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 8.21 g of(RS)-3-(ethoxycarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 100 ml of methanol was added 30 ml of an aqueous solution of 2.0 g ofpotassium hydroxide (85%) at room temperature, followed by stirring for6 hours. The reaction mixture was concentrated, and the concentrate wasdiluted with water, which was washed with chloroform. The aqueous layerwas adjusted to pH 2 by addition of 2N hydrochloric acid, and extractedwith chloroform, and the organic layer was dried over anhydrous sodiumsulfate and concentrated to yield 6.63 g (86%) of the title compound.

NMR (CDCl₃) δ: 7.74 (s, 1H), 7.35-6.70 (m, 10H), 4.73 (dd, J=4.4, 5.9Hz, 1H), 4.01 (dd, J=5.9, 14.6 Hz, 1H), 3.86-3.38 (m, 5H), 2.90 (d,J=15.9 Hz, 1H), 2.65 (d, J=15.9 Hz, 1H), 2.18 (s, 3H), 1.13 (t, J=6.8Hz, 3H), 1.08 (t, J=6.8 Hz, 3H).

Example 109(RS)-1-(2,2-Diethoxyethyl)-3-((N-methyl)-(N-phenyl)amino)carbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

In 50 ml of dichloromethane was dissolved 0.360 g of(RS)-1-(2,2-ethoxyethyl)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one,and 0.180 g of 4-dimethylaminopyridine, 0.180 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.095ml of N-methylaniline were successively added to the solution. Themixture was stirred for 8 hours, followed by concentration. The residuewas diluted with ethyl acetate and washed successively with dilutehydrochloric acid and saturated aqueous sodium hydrogencarbonate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The crude product was purified by silica gel column chromatography(hexane/ethyl acetate=2/1) to give 0.278 g (65%) of the title compoundas a white powder.

NMR (CDCl₃) δ: 7.83 (s, 1H), 7.39-6.83 (m, 12H), 6.63 (br, 2H), 4.55(dd, J=5.4, 5.8 Hz, 1H), 3.87 (dd, J=5.8, 14.2 Hz, 1H), 3.75-3.28 (m,5H), 3.24 (s, 3H), 2.64 (d, J=14.6 Hz, 1H), 2.27 (d, J=14.6 Hz, 1H),2.24 (s, 3H), 1.06 (t, J=6.8 Hz, 3H), 1.03 (t, J=6.8 Hz, 3H).

EXAMPLES 110 TO 137

The following compounds were prepared in the same manner as in Example109, except for using various amines in place of N-methylaniline used inExample 109 as a starting material.

Example 110(RS)-1-(2,2-Diethoxyethyl)-3-((4-methoxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 9.03 (s, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz,2H), 7.48-7.26 (m, 4H), 7.26-6.82 (m, 6H), 4.76 (dd, J=4.4, 6.0 Hz, 1H),3.99 (dd, J=6.0 Hz, 14.3 Hz, 1H), 3.89 (s, 3H), 3.89-3.40 (m, 5H), 3.01(d, J=15.2 Hz, 1H), 2.75 (d, J=15.2 Hz, 1H), 2.19 (s, 3H), 1.12 (t,J=7.0 Hz, 3H), 1.09 (t, J=6.8 Hz, 3H).

Example 111(RS)-1-(2,2-Diethoxyethyl)-3-((3-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.51 (s, 1H), 7.35-6.86 (m, 14H), 4.77 (dd, J=4.4, 5.9Hz, 1H), 4.01 (dd, J=5.9, 13.7 Hz, 1H), 3.85-3.40 (m, 5H), 2.98 (d,J=14.3 Hz, 1H), 2.64 (d, J=14.3 Hz, 1H), 2.27 (s, 3H), 2.20 (s, 3H),1.14 (t, J=7.4 Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

Example 112(RS)-1-(2,2-Diethoxyethyl)-3-((2-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.43 (s, 1H), 9.04 (s, 1H), 7.56 (s, 1H), 7.34-6.80 (m,12H), 4.77-4.65 (m, 1H), 3.86 (dd, J=5.7, 13.1 Hz, 1H), 3.76-3.40 (m,5H), 2.89 (d, J=14.3 Hz, 1H), 2.62 (d, J=14.3 Hz, 1H), 2.18 (s, 3H),2.06 (s, 3H).

Example 113(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-(n-propylaminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 7.41 (s, 1H), 7.34-6.90 (m, 9H), 6.28 (br, 1H), 4.78 (dd,J=4.4 Hz, 5.8 Hz, 1H), 4.00 (dd, J=5.8, 13.7 Hz, 1H), 3.89-3.44 (m, 5H),3.17 (br, 2H), 2.83 (d, J=14.8 Hz, 1H), 2.36 (d, J=14.8 Hz, 1H), 2.23(s, 3H), 1.47 (q, J=7.4 Hz, 2H), 1.18 (t, J=7.4 Hz, 3H), 1.11 (t, J=7.4Hz, 3H), 0.86 (t, J=7.4 Hz, 3H).

Example 114(RS)-3-((4-Chlorophenyl)aminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.79 (s, 1H), 7.40-6.80 (m, 14H), 4.74 (dd, J=4.4, 5.4Hz, 1H), 3.98 (dd, J=5.4, 14.2 Hz, 1H), 3.80-3.35 (m, 5H), 2.98 (d,J=14.6 Hz, 1H), 2.72 (d, J=14.6 Hz, 1H), 2.19 (s, 3H), 1.11 (t, J=7.4Hz, 3H), 1.09 (t, J=6.8 Hz, 3H).

Example 115(RS)-1-(2,2-Diethoxyethyl)-3-((4-methoxyphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.40-6.60 (m, 15H), 4.75 (dd, J=4.8, 5.8 Hz, 1H), 3.99(dd, J=5.8, 14.1 Hz, 1H), 3.88-3.40 (m, 5H), 3.64 (s, 3H), 2.86 (d,J=15.2 Hz, 1H), 2.58 (d, J=15.2 Hz, 1H), 2.27 (s, 3H), 1.17 (t, J=6.8Hz, 3H), 1.13 (t, J=7.4 Hz, 3H).

Example 116(RS)-3-((3-Ethoxycarbonylpropyl)aminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.40-6.70 (m, 10H), 6.40 (br, t, J=5.7 Hz, 1H), 4.78 (dd,J=4.4, 6.3 Hz, 1H), 4.18-3.90 (m, 3H), 3.86-3.47 (m, 5H), 3.38-3.20 (m,2H), 2.78 (d, J=14.2 Hz, 1H), 2.37 (d, J=14.2 Hz, 1H), 2.25 (s, 3H),1.90-1.75 (m, 2H), 1.33-1.05 (m, 11H).

Example 117(RS)-1-(2,2-Diethoxyethyl)-3-(methoxyaminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.33-6.80 (m, 9H), 6.68 (s, 1H), 6.62 (s, 1H), 4.76 (dd,J=4.4, 5.8 Hz, 1H), 3.98 (dd, J=5.8, 14.2 Hz, 1H), 3.86-3.40 (m, 5H),3.66 (s, 3H), 2.91 (d, J=15.0 Hz, 1H), 2.57 (d, J=15.0 Hz, 1H), 2.28 (s,3H), 1.17 (t, J=6.8 Hz, 3H), 1.13 (t, J=6.8 Hz, 3H).

Example 118(RS)-1-(2,2-Diethoxyethyl)-3-((4-methoxycarbonylmethylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.42 (s, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.28-6.80 (m, 12H),4.78 (dd, J=3.9, 5.7 Hz, 1H), 4.02 (dd, J=5.7, 14.3 Hz, 1H), 3.86-3.40(m, 5H), 3.69 (s, 3H), 3.58 (s, 2H), 2.94 (d, J=14.6 Hz, 1H), 2.55 (d,J=14.6 Hz, 1H), 2.23 (s, 3H), 1.16 (t, J=7.0 Hz, 3H), 1.11 (t, J=6.8 Hz,3H).

Example 119(RS)-1-(2,2-Diethoxyethyl)-3-((2,2-diethoxyethyl)aminocarbonylmethyl)-3-(N'-(4-methyl-phenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.35-6.81 (m, 9H), 6.80 (s, 1H), 6.20 (br, 1H), 4.77 (dd,J=4.4 Hz, 6.2 Hz, 1H), 4.49 (t, J=4.8 Hz, 1H), 4.00 (dd, J=6.2, 14.2 Hz,1H), 3.84-3.20 (m, 11H), 2.85 (d, J=14.6 Hz, 1H), 2.30 (d, J=14.6 Hz,1H), 2.24 (s, 3H), 1.30-0.95 (m, 12H).

Example 120(RS)-1-(2,2-Diethoxyethyl)-3-((4-hexylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.28 (s, 1H), 7.36-6.75 (m, 14H), 4.76 (dd, J=4.3, 5.7Hz, 1H), 3.99 (dd, J=5.7, 13.7 Hz, 1H), 3.85-3.40 (m, 5H), 2.96 (d,J=14.3 Hz, 1H), 2.59 (d, J=14.3 Hz, 1H), 2.53 (t, J=7.4 Hz, 2H), 2.22(s, 3H), 1.70-1.42 (m, 2H), 1.42-0.97 (m, 12H), 0.87 (t, J=5.7 Hz, 3H).

Example 121(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-((4-nitrophenyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 9.45 (s, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz,2H), 7.38-7.15 (m, 3H), 7.10-6.80 (m, 7H), 4.77 (dd, J=4.4, 5.8 Hz, 1H),4.01 (dd, J=5.8, 14.6 Hz, 1H), 3.79-3.40 (m, 5H), 3.06 (d, J=15.0 Hz,1H), 2.80 (d, J=15.0 Hz, 1H), 2.20 (s, 3H), 1.14 (t, J=6.8 Hz, 3H), 1.10(t, J=7.2 Hz, 3H).

Example 122(RS)-1-(2,2-Diethoxyethyl)-3-((3,4-dimethylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.44 (s, 1H), 7.30-6.85 (m, 13H), 4.77 (dd, J=4.4, 5.7Hz, 1H), 3.99 (dd, J=5.7, 14.9 Hz, 1H), 3.85-3.43 (m, 5H), 2.97 (d,J=15.2 Hz, 1H), 2.60 (d, J=15.2 Hz, 1H), 2.21 (s, 3H), 2.19 (s, 3H),2.16 (s, 3H), 1.15 (t, J=6.8 Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

Example 123(RS)-3-((3-Chlorophenyl)aminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.64 (s, 1H), 7.58 (s, 1H), 7.35-6.84 (m, 13H), 4.76 (dd,J=4.4, 5.7 Hz, 1H), 4.02 (dd, J=5.7, 13.7 Hz, 1H), 3.81-3.40 (m, 5H),2.99 (d, J=14.6 Hz, 1H), 2.72 (d, J=14.6 Hz, 1H), 2.21 (s, 3H), 1.14 (t,J=6.8 Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

Example 124(RS)-1-(2,2-Diethoxyethyl)-3-((4-fluorophenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.60 (s, 1H), 7.42-6.83 (m, 14H), 4.74 (dd, J=4.3, 5.7Hz, 1H), 3.98(dd, J=5.7, 14.3 Hz, 1H), 3.80-3.40 (m, 5H), 2.95 (d,J=14.3 Hz, 1H), 2.67 (d, J=14.3 Hz, 1H), 2.21 (s, 3H), 1.14 (t, J=7.2Hz, 3H), 1.10 (t, J=7.4 Hz, 3H).

Example 125(RS)-3-((4-Aminophenyl)aminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.38 (s, 1H), 7.35-6.80 (m, 12H), 6.53 (d, J=8.2 Hz, 2H),4.76 (dd, J=4.4, 5.9 Hz, 1H), 4.01 (dd, J=5.9, 13.7 Hz, 1H), 3.85-3.40(m, 5H), 2.91 (d, J=14.6 Hz, 1H), 2.56 (d, J=14.6 Hz, 1H), 2.20-1.70(br, 2H), 2.19 (s, 3H), 1.14 (t, J=7.0 Hz, 3H), 1.09 (t, J=7.4 Hz, 3H).

Example 126(RS)-3-(Benzylaminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 7.40-6.84 (m, 15H), 6.63 (t, J=5.4 Hz, 1H), 4.75 (dd,J=4.4, 5.7 Hz, 1H), 4.33 (d, J=5.4 Hz, 2H), 3.98 (dd, J=5.7 Hz, 14.3 Hz,1H), 3.84-3.39 (m, 5H), 2.86 (d, J=14.6 Hz, 1H), 2.44 (d, J=14.6 Hz,1H), 2.22 (s, 3H), 1.13 (t, J=6.8 Hz, 3H), 1.08 (t, J=7.4 Hz, 3H).

Example 127(RS)-1-(2,2-Diethoxyethyl)-3-((4-hydroxyphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 9.72 (s, 1H), 9.09 (s, 1H), 9.07 (s, 1H), 8.13 (s, 1H),7.67 (s, 1H), 7.33-6.83 (m, 9H), 6.68 (d, J=8.8 Hz, 1H), 4.81-4.69 (m,1H), 3.88(dd, J=5.7, 14.3 Hz, 1H), 3.80-3.40 (m, 5H), 2.80 (d, J=14.0Hz, 1H), 2.44 (d, J=14.0 Hz, 1H), 2.19 (s, 3H), 1.16 (t, J=7.4 Hz, 3H),1.11 (t, J=7.4 Hz, 3H).

Example 128(RS)-1-(2,2-Diethoxyethyl)-3-((4-trifluoromethylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.87 (s, 1H), 7.56 (dd, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz,2H), 7.27 (t, J=7.8 Hz, 2H), 7.18-6.85 (m, 8H), 4.77 (dd, J=4.6 Hz, 5.7Hz, 1H), 4.01 (dd, J=5.7, 13.1 Hz, 1H), 3.83-3.45 (m, 5H), 2.99 (d,J=14.8 Hz, 1H), 2.71 (d, J=14.8 Hz, 1H), 2.22 (s, 3H), 1.15 (t, J=6.8Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

Example 129(RS)-1-(2,2-Diethoxyethyl)-3-((3-methoxyphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.35-8.14 (m, 1H), 7.34-6.90 (m, 12H), 6.90-6.63 (m, 2H),4.78 (dd, J=3.8, 5.7 Hz, 1H), 4.02 (dd, J=5.7, 13.7 Hz, 1H), 3.77 (s,3H), 3.85-3.45 (m, 5H), 2.97 (d, J=14.2 Hz, 1H), 2.54 (d, J=14.2 Hz,1H), 2.24 (s, 3H), 1.18 (t, J=6.8 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H).

Example 130(RS)-1-(2,2-Diethoxyethyl)-3-((4-(N,N-dimethylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.31 (s, 1H), 7.33-6.85 (m, 12H), 6.61 (d, J=8.8 Hz, 2H),4.78 (dd, J=3.9, 5.7 Hz, 1H), 4.00 (dd, J=5.7 Hz, 14.3 Hz, 1H),3.85-3.40 (m, 5H), 2.94 (d, J=14.6 Hz, 1H), 2.89 (s, 6H), 2.55 (d,J=14.6 Hz, 1H), 2.22 (s, 3H), 1.16 (t, J=6.8 Hz, 3H), 1.11 (t, J=7.4 Hz,3H).

Example 131(RS)-1-(2,2-Diethoxyethyl)-3-((4-(N-trifluoromethylcarbonyl-N-methylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.83 (s, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.36-7.17 (m, 3H),7.16-6.87 (m, 9H), 4.78 (dd, J=4.3, 5.9 Hz, 1H), 4.01 (dd, J=5.9 Hz,14.2 Hz, 1H), 3.82-3.50 (m, 5H), 3.29 (s, 3H), 2.95 (d, J=14.8 Hz, 1H),2.66 (d, J=14.8 Hz, 1H), 2.22 (s, 3H), 1.15 (t, J=6.9 Hz, 3H), 1.10 (t,J=6.9 Hz, 3H).

Example 132(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-((2-pyrimidinyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.42 (d, J=5.0 Hz, 2H), 7.79 (br, 1H), 7.46-6.80 (m,11H), 4.84 (dd, J=4.4, 5.9 Hz, 1H), 4.04 (dd, J=5.9 Hz, 14.2 Hz, 1H),3.88 (dd, J=4.4, 14.2 Hz, 1H), 3.81-3.47 (m, 4H), 3.16 (br, 2H), 2.20(s, 3H), 1.18 (t, J=7.0 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H).

Example 133(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-(phenylaminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.49 (s, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.35-6.86 (m, 13H),4.77 (dd, J=4.4, 5.9 Hz, 1H), 4.00 (dd, J=5.9, 14.1 Hz, 1H), 3.85-3.40(m, 5H), 2.97 (d, J=14.6 Hz, 1H), 2.64 (d, J=14.6 Hz, 1H), 2.21 (s, 3H),1.14 (t, J=7.3 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).

Example 134(RS)-1-(2,2-Diethoxyethyl)-3-((4-(N,N-diethylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.18 (s, 1H), 7.38-6.77 (m, 12H), 6.55 (d, J=9.4 Hz, 2H),4.78 (dd, J=4.4, 5.8 Hz, 1H), 4.02 (dd, J=5.8 Hz, 14.2 Hz, 1H),3.85-3.41 (m, 5H), 3.29 (q, J=6.8 Hz, 4H), 2.95 (d, J=14.6 Hz, 1H), 2.53(d, J=14.6 Hz, 1H), 2.21 (s, 3H), 1.22-0.92 (m, 12H).

Example 135(RS)-1-(2,2-Diethoxyethyl)-3-((4-trifluoromethylcarbonylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.88 (s, 1H), 8.27 (s, 1H), 7.43-7.12 (m, 7H), 7.12-6.77(m, 7H), 4.78 (dd, J=3.9, 5.8 Hz, 1H), 4.03 (dd, J=5.8 Hz, 14.6 Hz, 1H),3.84-3.39 (m, 5H), 2.95 (d, J=14.8 Hz, 1H), 2.72 (d, J=14.8 Hz, 1H),2.19 (s, 3H), 1.14 (t, J=7.0 Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

Example 136(RS)-1-(2,2-Diethoxyethyl)-3-(((1-trifluoromethylcarbonyl)indolin-5-yl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.99 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.54 (s, 1H),7.40-6.80 (m, 11H), 4.79 (dd, J=3.8, 5.9 Hz, 1H), 4.22-3.94 (m, 3H),3.88-3.41 (m, 5H), 3.13-2.86 (m, 3H), 2.77 (d, J=15.1 Hz, 1H), 2.19 (s,3H), 1.15 (t, J=6.8 Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

Example 137(RS)-1-(2,2-Diethoxyethyl)-3-((5-indolylamino))carbonylethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.72 (s, 1H), 8.27 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H),7.33 (s, 1H), 7.24-6.72 (m, 11H), 6.32 (s, 1H), 4.79-4.67 (m, 1H), 3.99(dd, J=5.5 Hz, 14.6 Hz, 1H), 3.84-3.38 (m, 5H), 2.87 (d, J=14.6 Hz, 1H),2.49 (d, J=14.6 Hz, 1H), 2.13 (s, 3H), 1.08 (t, J=6.8 Hz, 3H), 1.05 (t,J=6.8 Hz, 3H).

Example 138(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-((5-methylpyrido-2-yl)aminocarbonylmethyl)indolin-2-one

To a solution of 0.223 g of(RS)-1-(2,2-diethoxyethyl)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 15 ml of dichloromethane were added successively 0.140 g of4-dimethylaminopyridine and 0.040 ml of thionyl chloride at 0° C.,followed by stirring at 0° C. for 30 minutes. To the mixture werefurther added 0.070 g of 4-dimethylaminopyridine and 0.130 g of6-amino-3-picoline at 0° C. The resulting mixture was stirred at roomtemperature for 1 hour, and then washed with an aqueous solution ofsodium chloride. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=2/1) to give 0.169 g (73%)of the title compound.

NMR (CDCl₃) δ: 9.01 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.93 (s, 1H), 7.46(dd, J=2.6, 8.8 Hz, 1H), 7.30-6.87 (m, 10H), 4.77 (dd, J=4.4, 6.2 Hz,1H), 3.97 (dd, J=6.2, 14.2 Hz, 1H), 3.87-3.42 (m, 5H), 3.06 (d, J=14.2Hz, 1H), 2.57 (d, J=14.2 Hz, 1H), 2.25 (s, 3H), 2.23 (s, 3H), 1.14 (t,J=7.4 Hz, 3H), 1.11 (t, J=7.2 Hz, 3H).

EXAMPLES 139 TO 145

The following compounds were prepared in the same manner as in Example138, except for using various amines in place of 6-amino-3-picoline usedin Example 138.

Example 139(RS)-3-((2-Chlorophenyl)aminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.15 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.35-6.85 (m, 13H),4.78 (dd,J=4.4, 5.8 Hz, 1H), 4.02 (dd, J=5.8 Hz, 14.3 Hz, 1H), 3.85-3.40(m, 5H), 3.10 (d, J=14.6 Hz, 1H), 2.62 (d, J=14.6 Hz, 1H), 2.24 (s, 3H),1.14 (t, J=7.0 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H).

Example 140(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-((4-pyridylamino)carbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 9.68 (s, 1H), 8.32 (d, J=5.8 Hz, 2H), 7.73 (s, 1H),7.45-6.80 (m, 11H), 4.77 (dd, J=4.6, 5.7 Hz, 1H), 4.02 (dd, J=5.7 Hz,14.3 Hz, 1H), 3.85-3.40 (m, 5H), 2.99 (d, J=15.0 Hz, 1H), 2.74 (d,J=15.0 Hz, 1H), 2.20 (s, 3H), 1.14 (t, J=7.0 Hz, 3H), 1.10 (t, J=7.4 Hz,3H).

Example 141(RS)-1-(2,2-Diethoxyethyl)-3-((2-methoxyphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.22 (dd, J=1.4 Hz, 7.8 Hz, 1H), 7.88 (s, 1H), 7.40-6.75(m, 13H), 4.78 (dd, J=4.4, 5.8 Hz, 1H), 4.03 (dd, J=5.8 Hz, 13.7 Hz,1H), 3.74 (s, 3H), 3.90-3.43 (m, 5H), 3.12 (d, J=14.6 Hz, 1H), 2.53 (d,J=14.6 Hz, 1H), 2.21 (s, 3H), 1.15 (t, J=7.4 Hz, 3H), 1.12 (t, J=6.8 Hz,3H).

Example 142(RS)-1-(2,2-Diethoxyethyl)-3-((2-hydroxy-4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.57 (s, 1H), 8.65-8.20 (br, 1H), 7.32-7.15 (m, 3H),7.15-6.79 (m, 8H), 6.73 (s, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.73 (dd,J=4.9, 5.7 Hz, 1H), 4.01 (dd, J=5.7, 14.3 Hz, 1H), 3.80-3.43 (m, 5H),2.87 (d, J=14.3 Hz, 1H), 2.72 (d, J=14.3 Hz, 1H), 2.21 (s, 3H), 2.19 (s,3H), 1.11 (t, J=6.8 Hz, 3H), 1.08 (t, J=7.4 Hz, 3H).

Example 143(RS)-1-(2,2-Diethoxyethyl)-3-((2-methoxypyrido-5-yl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.61 (s, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.65 (dd, J=3.0 Hz,8.8 Hz, 1H), 7.35-6.79 (m, 10H), 6.61 (d, J=8.8 Hz, 1H), 4.76 (dd,J=3.0, 5.7 Hz, 1H), 4.00 (dd, J=5.7 Hz, 14.3 Hz, 1H), 3.87 (s, 3H),3.87-3.38 (m, 5H), 2.96 (d, J=14.3 Hz, 1H), 2.68 (d, J=14.3 Hz, 1H),2.20 (s, 3H), 1.13 (t, J=7.2 Hz, 3H), 1.09 (t, J=7.0 Hz, 3H).

Example 144(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-((2-pyridyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 8.97 (brs, 1H), 8.14 (d, J=4.9 Hz, 1H), 8.08 (d, J=7.9Hz, 1H), 7.65 (t, J=7.3 Hz, 1H), 7.35-6.85 (m, 11H), 4.77 (dd, J=4.3,5.9 Hz, 1H), 3.99 (dd, J=5.9 Hz, 14.2 Hz, 1H), 3.90-3.47 (m, 5H), 3.10(d, J=14.8 Hz, 1H), 2.61 (d, J=14.8 Hz, 1H), 2.23 (s, 3H), 1.14 (t,J=6.9 Hz, 3H), 1.11 (t, J=7.3 Hz, 3H).

Example 145(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido-3-((3-pyridyl)aminocarbonylmethyl)indolin-2-one

NMR (CDCl₃) δ: 9.21 (s, 1H), 8.61 (d, J=2.6 Hz, 1H), 8.26 (d, J=4.6 Hz,1H), 7.90 (d, J=7.9 Hz, 1H), 7.64 (s, 1H), 7.38-6.94 (m, 10H), 4.77 (dd,J=4.3, 5.9 Hz, 1H), 4.03 (dd, J=5.9 Hz, 14.5 Hz, 1H), 3.85-3.45 (m, 5H),3.01 (d, J=14.8 Hz, 1H), 2.74 (d, J=14.8 Hz, 1H), 2.20 (s, 3H), 1.13 (t,J=6.9 Hz, 3H), 1.09 (t, J=7.3 Hz, 3H).

Example 146(RS)-3-(Ethoxycarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 107,except for starting with(RS)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-onein place of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 107.

NMR (CDCl₃) δ: 7.32-6.90 (m, 9H), 6.56 (dd, J=1.8, 8.2 Hz, 1H),4.79-4.75 (m, 1H), 4.11 (q, J=6.3 Hz, 2H), 4.01 (dd, J=6.0, 14.2 Hz,1H), 3.82-3.65 (m, 5H), 3.73 (s, 3H), 2.93 (d, J=15.2 Hz, 1H), 2.55 (d,J=15.2 Hz, 1H), 1.20-1.05 (m, 9H).

Example 147(RS)-1-(2,2-Diethoxyethyl)-3-(hydroxycarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 108,except for starting with(RS)-3-(ethoxycarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-onein place of(RS)-3-(ethoxycarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneas used in Example 108.

NMR (CDCl₃) δ: 7.85 (s, 1H), 7.29-7.20 (m, 3H), 7.06-6.92 (m, 5H), 6.69(d, J=8.9 Hz, 1H), 6.48 (dd, J=2.2, 8.3 Hz, 1H), 4.77-4.74 (m, 1H), 4.04(dd, J=6.1, 14.5 Hz, 1H), 3.79-3.49 (m, 5H), 3.61 (s, 3H), 2.90 (d, 15.8Hz, 1H), 2.70 (d, 15.8 Hz, 1H), 1.17-1.08 (m, 6H).

Example 148(RS)-1-(2,2-Diethoxyethyl)-3-((4-methoxyphenyl)aminocarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

To a solution of 0.50 g of(RS)-1-(2,2-diethoxyethyl)-3-(hydroxycarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-onein 50 ml of dichloromethane were added successively 0.140 g of4-dimethylaminopyridine and 0.090 ml of thionyl chloride at 0° C.,followed by stirring at 0° C. for 30 minutes. To the mixture werefurther added 0.140 g of 4-dimethylaminopyridine and 0.190 g of4-methoxyaniline at 0° C. The resulting mixture was stirred at roomtemperature for 1 hour, and then washed with an aqueous solution ofsodium chloride. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=2/1) to give 0.54 g (88%) ofthe title compound.

Rf=0.76 (dichloromethane/methanol=10/1)

NMR (CDCl₃) δ: 8.51 (s, 1H), 7.45-6.44 (m, 14H), 4.78 (dd, J=4.4, 5.9Hz, 1H), 3.98 (dd, J=5.9, 14.2 Hz, 1H), 3.84-3.47 (m, 5H), 3.74 (s, 3H),3.63 (s, 3H), 2.97 (d, J=14.8 Hz, 1H), 2.63 (d, J=14.8 Hz, 1H), 1.15 (t,J=6.9 Hz, 3H), 1.09 (t, J=6.9 Hz, 3H).

EXAMPLES 149 TO 158

The following compounds were prepared in the same manner as in Example148, except for using various amines in place of 4-methoxyaniline usedin Example 148.

Example 149(RS)-3-((4-Chlorophenyl)aminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

Rf=0.76 (dichloromethane/methanol=10/1)

NMR (CDCl₃) δ: 8.80 (s, 1H), 7.55 (s, 1H), 7.33-6.90 (m, 11H), 6.67 (d,J=9.2 Hz, 1H), 6.45 (dd, J=2.0, 8.2 Hz, 1H), 4.76 (dd, J=4.0, 5.6 Hz,1H), 3.99 (dd, J=5.6, 14.2 Hz, 1H), 3.79-3.49 (m, 5H), 3.61 (s, 3H),2.99 (d, J=14.8 Hz, 1H), 2.71 (d, J=14.8 Hz, 1H), 1.13 (t, J=6.9 Hz,3H), 1.09 (t, J=6.9 Hz, 3H).

Example 150(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((2-methylphenyl)aminocarbonylmethyl)indolin-2-one

Rf=0.25 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 8.85 (s, 1H), 7.76 (s, 1H), 7.46-7.43 (m, 1H), 7.25-6.95(m, 10H), 6.69 (d, J=7.9 Hz, 1H), 6.44 (d, J=8.3 Hz, 1H), 4.75 (dd,J=4.3, 5.9 Hz, 1H), 3.97 (dd, J=5.9, 14.5 Hz, 1H), 3.81-3.44 (m, 5H),3.61 (s, 3H), 3.00 (d, J=14.9 Hz, 1H), 2.75 (d, J=14.9 Hz, 1H), 2.14 (s,3H), 1.10 (t, J=6.6 Hz, 3H), 1.07 (t, J=6.6 Hz, 3H).

Example 151(RS)-1-(2,2-Diethoxyethyl)-3-((3-methoxyphenyl)aminocarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

Rf=0.06 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 8.72 (s, 1H), 7.62 (s, 1H), 7.30-6.92 (m, 10H), 6.69 (d,J=9.2 Hz, 1H), 6.61 (dd, J=2.3, 8.2 Hz, 1H), 6.43 (dd, J=2.3, 7.9 Hz,1H), 4.75 (dd, J=4.3, 5.9 Hz, 1H), 3.94 (dd, J=5.9, 14.2 Hz, 1H),3.80-3.43 (m, 5H), 3.67 (s, 3H), 3.59 (s, 3H), 3.00 (d, J=14.9 Hz, 1H),2.69 (d, J=14.9 Hz, 1H), 1.12 (t, J=6.9 Hz, 3H), 1.07 (t, J=6.9 Hz, 3H).

Example 152(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((3-methylphenyl)aminocarbonylmethyl)indolin-2-one

Rf=0.25 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 8.66 (s, 1H), 7.57 (s, 1H), 7.28-6.87 (m, 11H), 6.68 (d,J=7.9 Hz, 1H), 6.44 (d, J=8.2 Hz, 1H), 4.76 (dd, J=4.3, 5.9 Hz, 1H),3.96 (dd, J=5.9, 14.5 Hz, 1H), 3.81-3.42 (m, 5H), 3.60 (s, 3H), 3.00 (d,J=14.9 Hz, 1H), 2.69 (d, J=14.9 Hz, 1H), 2.22 (s, 3H), 1.13 (t, J=6.9Hz, 3H), 1.08 (t, J=6.9 Hz, 3H).

Example 153(RS)-1-(2,2-Diethoxyethyl)-3-((2-methoxyphenyl)aminocarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

Rf=0.10 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 8.20 (d, J=7.9 Hz, 1H), 7.90 (s, 1H), 7.73 (s, 1H), 7.42(s, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.22 (t, J=8.2 Hz, 1H), 7.09-6.71 (m,8H), 6.44 (d, J=6.6 Hz, 1H), 4.78 (dd, J=4.3, 5.9 Hz, 1H), 4.00 (dd,J=5.9, 14.2 Hz, 1H), 3.83-3.49 (m, 5H), 3.70 (s, 3H), 3.60 (s, 3H), 3.17(d, J=14.5 Hz, 1H), 2.57 (d, J=14.5 Hz, 1H), 1.14 (t, J=6.9 Hz, 3H),1.10 (t, J=6.9 Hz, 3H).

Example 154(RS)-1-(2,2-Diethoxyethyl)-3-((4-fluorophenyl)aminocarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

Rf=0.16 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 8.70 (s, 1H), 7.65 (s, 1H), 7.31-6.84 (m, 11H), 6.68 (d,J=7.9 Hz, 1H), 6.44 (d, J=6.6 Hz, 1H), 4.75 (dd, J=4.3, 5.6 Hz, 1H),3.96 (dd, J=5.6, 14.2 Hz, 1H), 3.80-3.45 (m, 5H), 3.59 (s, 3H), 3.00 (d,J=14.9 Hz, 1H), 2.73 (d, J=14.9 Hz, 1H), 1.11 (t, J=6.9 Hz, 3H), 1.07(t, J=6.9 Hz, 3H).

Example 155(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-(n-propylaminocarbonylmethyl)indolin-2-one

Rf=0.09 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 7.84 (s, 1H), 7.44 (s, 1H), 7.31-6.96 (m, 6H), 6.76 (d,J=8.6 Hz, 1H), 6.55 (t, J=5.6 Hz, 1H), 6.44 (dd, J=2.3, 8.3 Hz, 1H),4.79 (dd, J=4.3, 6.3 Hz, 1H), 3.98 (dd, J=6.3, 14.2 Hz, 1H), 3.86-3.50(m, 5H), 3.63 (s, 3H), 3.17-3.06 (m, 2H), 2.89 (d, J=14.5 Hz, 1H), 2.50(d, J=14.5 Hz, 1H), 1.40 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 1.09 (t, J=6.9Hz, 3H), 0.81 (t, J=7.3 Hz, 3H).

Example 156(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-(N,N'-dimethylaminophenyl)aminocarbonylmethyl)indolin-2-one

Rf=0.21 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 8.58 (s, 1H), 7.78 (s, 1H), 7.37 (s, 1H), 7.26-6.90 (m,8H), 6.67 (d, J=7.9 Hz, 1H), 6.54 (d, J=8.9 Hz, 2H), 6.41 (d, J=9.9 Hz,1H), 4.79-4.73 (m, 1H), 3.96 (dd, J=5.9, 14.2 Hz, 1H), 3.84-3.45 (m,5H), 3.58 (s, 3H), 2.97 (d, J=14.5 Hz, 1H), 2.83 (s, 6H), 2.65 (d,J=14.5 Hz, 1H), 1.12 (t, J=6.9 Hz, 3H), 1.07 (t, J=6.9 Hz, 3H).

Example 157(RS)-1-(2,2-Diethoxyethyl)-3-((4-methoxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

Rf=0.27 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 9.10 (s, 1H), 7.88 (s, 1H), 7.83 (d, J=8.6 Hz, 2H), 7.46(d, J=8.6 Hz, 2H), 7.32-7.17 (m, 3H), 7.01-6.90 (m, 4H), 6.68 (d, J=7.9Hz, 1H), 6.42 (dd, J=2.3, 8.3 Hz, 1H), 4.75 (dd, J=4.3, 5.9 Hz, 1H),3.95 (dd, J=5.9, 14.2 Hz, 1H), 3.85 (s, 3H), 3.80-3.44 (m, 5H), 3.56 (s,3H), 3.05 (d, J=15.2 Hz, 1H), 2.74 (d, J=15.2 Hz, 1H), 1.09 (t, J=6.9Hz, 3H), 1.06 (t, J=6.9 Hz, 3H).

Example 158(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((5-methylpyrido-2-yl)aminocarbonylmethyl)indolin-2-one

Rf=0.24 (dichloromethane/methanol=100/3)

NMR (CDCl₃) δ: 9.48 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.79 (s, 1H), 7.73(s, 1H), 7.41-6.90 (m, 8H), 6.71 (d, J=7.9 Hz, 1H), 6.46 (d, J=8.3 Hz,1H), 4.78-4.75 (m, 1H), 3.90 (br, 2H), 3.72-3.45 (m, 4H), 3.62 (s, 3H),3.10 (d, J=14.5 Hz, 1H), 2.61 (d, J=14.5 Hz, 1H), 2.21 (s, 3H), 1.13 (t,7.3 Hz, 3H), 1.07 (t, 7.3 Hz, 3H).

Example 159(RS)-1-(Formylmethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

To a solution of 1.61 g of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-onein 40 ml of acetone were added 10 ml of water and 1 ml of concentratedhydrochloric acid, and the mixture was heated under reflux for 2 hours.The reaction mixture was poured into water, and the thus formedprecipitate was collected by filtration and washed with ethyl ether toobtain 1.11 g (79%) of the title compound.

NMR (DMSO-d₆) δ: 10.06 (s, 1H), 9.66 (s, 1H), 9.32 (s, 1H), 7.75 (s,1H), 7.44 (d, J=8.3 Hz, 2H), 7.28-6.82 (m, 8H), 6.82 (d, J=8.3 Hz, 1H),6.44 (dd, J=2.0, 7.8 Hz, 1H), 4.77 (d, J=18.5 Hz, 1H), 4.60 (d, J=18.5Hz, 1H), 3.66 (s, 3H), 2.89 (d, J=14.6 Hz, 1H), 2.60 (d, J=14.1 Hz, 1H),2.26 (s, 3H).

Example 160(RS)-3-(N'-(3-Methoxyphenyl)ureido)-1-(2-(N,N-dimethylamino)ethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

To a solution of 0.386 g of(RS)-1-(formylmethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-onein 50 ml of methanol was added 0.8 g of dimethylamine hydrochloride atroom temperature, and 1.0 g of sodium cyanoborohydride was then addedthereto. The mixture was stirred at room temperature for 1 day, followedby concentration. The concentrate was diluted with dichloromethane andwashed with an aqueous solution of sodium chloride. The organic layerwas dried over anhydrous sodium sulfate and concentrated. The crudeproduct was washed with dichloromethane to afford 0.107 g (26%) of thetitle compound.

NMR (CDCl₃) δ: 10.21 (s, 1H), 9.26 (s, 1H), 7.62 (s, 1H), 7.32-6.84 (m,10H), 6.79 (d, J=8.3 Hz, 1H), 6.44 (dd, J=1.9, 7.8 Hz, 1H), 3.94-3.59(m, 2H), 3.65 (s, 3H), 2.82 (d, J=14.6 Hz, 1H), 2.62-2.08 (m, 3H), 2.25(s, 9H).

Example 161(RS)-1-(2,2-Diethoxyethyl)-3-((4-(N-methylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.475 g of(RS)-1-(2,2-diethoxyethyl)-3-((4-trifluoromethylcarbonyl-N-methylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 50 ml of methanol was added 10 ml of an aqueous solution of 0.50 g ofpotassium carbonate at room temperature, and the mixture was stirred for1 day, followed by concentration. The residue was diluted with water andextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate and concentrated. The crude product wasrecrystallized from chloroform to afford 0.26 g (65%) of the titlecompound.

NMR (DMSO-d₆) δ: 9.67 (s, 1H), 9.16 (s, 1H), 7.68 (s, 1H), 7.27-7.06 (m,7H), 6.98-6.89 (m, 3H), 6.47 (d, J=8.8 Hz, 2H), 5.49 (q, J=5.9 Hz, 1H),4.76-4.67 (m, 1H), 3.86 (dd, J=5.6, 13.8 Hz, 1H), 3.76-3.46 (m, 5H),2.76 (d, J=14.2 Hz, 1H), 2.64 (d, J=5.9 Hz, 3H), 2.41 (d, J=14.2 Hz,1H), 2.17 (s, 3H), 1.12 (t, J=6.9 Hz, 3H), 1.07 (t, J=5.0 Hz, 3H).

Example 162(RS)-1-(2,2-Diethoxyethyl)-3-((5-indolinyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 161,except for starting with(RS)-1-(2,2-diethoxyethyl)-3-(((1-trifluoromethylcarbonyl)indolin-5-yl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein place of(RS)-1-(2,2-diethoxyethyl)-3-((4-(N-trifluoromethylcarbonyl-N-methylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 161.

NMR (DMSO-d₆) δ: 9.67 (s, 1H), 9.15 (s, 1H), 7.68 (s, 1H), 7.36-6.86 (m,10H), 6.41 (d, J=8.6 Hz, 1H), 5.35 (s, 1H), 4.77-4.67 (m, 1H), 3.85 (dd,J=5.9, 14.2 Hz, 1H), 3.76-3.24 (m, 7H), 2.87 (t, J=8.3 Hz, 2H), 2.75 (d,J=14.2 Hz, 1H), 2.41 (d, J=14.2 Hz, 1H), 2.17 (s, 3H), 1.11 (t, J=6.9Hz, 3H), 1.07 (t, J=6.9 Hz, 3H).

Example 163(RS)-1-(2,2-Diethoxyethyl)-3-((4-hydroxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.588 g of(RS)-1-(2,2-diethoxyethyl)-3-((4-methoxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 30 ml of methanol was added 5 ml of an aqueous solution of 0.20 g ofpotassium hydroxide (85%) at room temperature. The mixture was stirredfor 1 day, followed by concentration. The concentrate was diluted withwater, and washed with chloroform. The aqueous layer was adjusted to pH2 with 2N hydrochloric acid and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The resulting crude product was purified by silica gel columnchromatography (hexane/ethyl acetate 1/1) to give 0.56 g (98%) of thetitle compound.

NMR (DMSO-d₆) δ: 12.95-12.45 (br, 1H), 10.33 (s, 1H), 9.05 (s, 1H), 7.89(d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 7.30-6.83 (m,8H), 4.76-4.66 (m, 1H), 3.86 (dd, J=5.7, 13.7 Hz, 1H), 3.78-3.40 (m,5H), 2.94 (d, J=14.6 Hz, 1H), 2.58 (d, J=14.6 Hz, 1H), 2.18 (s, 3H),1.11 (t, J=6.8 Hz, 3H), 1.08 (t, J=6.8 Hz, 3H).

Example 164(RS)-1-(2,2-Diethoxyethyl)-3-((4-hydroxycarbonylmethylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner in Example 163,except for starting with(RS)-1-(2,2-diethoxyethyl)-3-((4-methoxycarbonylmethylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onein place of(RS)-1-(2,2-diethoxyethyl)-3-((4-methoxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 163.

NMR (CDCl₃) δ: 8.73 (s, 1H), 7.55-7.37 (br, 1H), 7.32-6.77 (m, 14H),4.85-4.74 (m, 1H), 4.08 (dd, J=5.7, 14.3 Hz, 1H), 3.85-3.35 (m, 7H),2.95 (d, J=15.2 Hz, 1H), 2.64 (d, J=15.2 Hz, 1H), 2.17 (s, 3H), 1.15 (t,J=6.4 Hz, 3H), 1.11 (t, J=6.8 Hz, 3H).

Example 165(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-hydroxycarbonylphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

The title compound was prepared in the same manner as in Example 163,except for starting with(RS)-3-(N'-(4-ethoxycarbonylphenyl)ureido)-1(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-onein place of(RS)-1-(2,2-diethoxyethyl)-3-((4-methoxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 163.

Rf=0.05 (n-hexane/ethyl acetate=1/1)

NMR (DMSO-d₆) δ: 9.97 (s, 1H), 9.64 (s, 1H), 7.84 (s, 1H), 7.75 (d,J=8.3 Hz, 2H), 7.44-6.89 (m, 1H), 4.75 (dd, J=4.0, 5.4 Hz, 1H), 3.88(dd, J=5.4, 13.2 Hz, 1H), 3.74-3.22 (m, 5H), 2.86 (d, J=15.1 Hz, 1H),2.51 (d, J=15.1 Hz, 1H), 2.27 (s, 3H), 1.14 (t, J=7.3 Hz, 3H), 1.10 (t,J=7.3 Hz, 3H).

Example 166(RS)-3-(N'-(4-Aminophenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

A suspension of 0.62 g of(RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-nitrophenyl)ureido)indolin-2-oneand 20 mg of 5% Pd/C in 100 ml of ethanol was stirred at roomtemperature for 12 hours under a hydrogen atmosphere. The reactionmixture was filtered through Cerite, and the filtrate was concentrated.The residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1) to give 0.33 g (57%) of the title compound.

NMR (CDCl₃) δ: 8.31 (s, 1H), 7.33-6.94 (m, 11H), 6.62 (s, 1H), 6.50 (d,J=8.3 Hz, 2H), 4.75 (dd, J=4.4, 5.9 Hz, 1H), 4.00 (dd, J=5.9, 14.1 Hz,1H), 3.79-3.52 (m, 7H), 2.92 (d, J=14.6 Hz, 1H), 2.51 (d, J=14.6 Hz,1H), 2.30 (s, 3H), 1.16 (t, J=7.3 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).

Example 167(RS)-1-(2,2-Diethoxyethyl)-3-(N'-(4-dimethylaminophenyl)ureido-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one

To a solution of 0.148 g of(RS)-3-(N'-(4-aminophenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-onein 20 ml of methanol were added successively 0.1 ml of a formalinaqueous solution and 0.104 g of sodium cyanoborohydride. The mixture wasneutralized with 2N hydrochloric acid, and Molecular Sieves 4A was addedthereto, followed by stirring at room temperature for 3 hours. Thereaction mixture was filtered through Cerite, and the filtrate wasconcentrated. The concentrate was diluted with ethyl acetate and washedwith a saturated aqueous sodium hydrogencarbonate. The organic layer wasdried over anhydrous sodium sulfate and concentrated. The resultingcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=1/1) to give 0.120 g (77%) of the title compound.

Rf=0.11 (hexane/ethyl acetate=1/1)

NMR (CDCl₃) δ: 8.32 (s, 1H), 7.35-6.54 (m, 13H), 6.41 (s, 1H), 4.76 (dd,J=3.9, 6.3 Hz, 1H), 3.99 (dd, J=6.3, 13.7 Hz, 1H), 3.81-3.53 (m, 5H),2.91 (d, J=15.1 Hz, 1H), 2.89 (s, 6H), 2.51 (d, J=15.1 Hz, 1H), 2.31 (s,3H), 1.16 (t, J=6.3 Hz, 3H), 1.11 (t, J=6.3 Hz, 3H).

EXAMPLES 168 TO 170

The following compounds were prepared in the same manner as in Example71, except for using(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one,used in Example 71, with the (4-methylphenyl)ureido moiety replaced withvarious substituted ureides as a starting material and replacingN-p-tolyl-2-bromoacetamide used in Example 71 with variousbromoacetamide derivatives as a reactant.

Example 168(RS)-3-((4-Chlorophenyl)aminocarbonylmethyl)-3-(N'-(4-chlorophenyl)ureido)-1-(2,2-diethoxyethyl)indolin-2-one

Rf=0.29 (n-hexane/ethyl acetate=1/1)

NMR (CDCl₃) δ: 8.51 (s, 1H), 7.44-7.00 (m, 14H), 4.78 (dd, J=4.9, 5.4Hz, 1H), 4.04 (dd, J=5.4, 14.2 Hz, 1H), 3.83-3.48 (m, 5H), 2.99 (d,J=14.6 Hz, 1H), 2.68 (d, J=14.6 Hz, 1H), 2.00-1.08 (m, 6H).

Example 169(RS)-3-((4-Chlorophenyl)aminocarbonylmethyl)-1-(2,2-diethoxyethyl)-3-(N'-(4-methoxyphenyl)ureido)indolin-2-one

NMR (DMSO-d₆) δ: 10.14 (s, 1H), 8.98 (s, 1H), 7.57-6.70 (m, 13H), 4.72(dd, J=4.3, 5.9 Hz, 1H), 3.84 (dd, J=5.9, 14.4 Hz, 1H), 3.71-3.50 (m,5H), 3.66 (s, 3H), 2.88 (d, J=14.8 Hz, 1H), 2.52 (d, J=14.8 Hz, 1H),1.11 (t, J=7.8 Hz, 3H), 1.08 (t, J=7.3 Hz, 3H).

Example 170(RS)-1-(2,2-Diethoxyethyl)-3-((4-fluorophenyl)aminocarbonylmethyl)-3-(N'-(4-fluorophenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.40 (s, 1H), 7.42-6.78 (m, 14H), 4.78 (dd, J=4.3, 5.9Hz, 1H), 4.02 (dd, J=5.9, 14.5 Hz, 1H), 3.81-3.52 (m, 5H), 2.98 (d,J=14.5 Hz, 1H), 2.63 (d, J=14.5 Hz, 1H), 1.17 (t, J=6.9 Hz, 3H), 1.12(t, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 26 L-Menthyl Bromoacetate and D-Menthyl Bromoacetate

To a solution of 83.4 g of bromoacetic acid and 78.1 g of L- (orD-)menthol in 1 2 of toluene was added 300 mg of p-toluenesulfonic acid,and the mixture was refluxed for 6 hours while azeotropically removingproduced water together with toluene. The reaction mixture was washedwith saturated aqueous sodium hydrogencarbonate, and the organic layerwas dried over anhydrous sodium sulfate and concentrated. The residuewas distilled under reduced pressure to obtain 128 g (93%) of the titledcompound.

NMR (CDCl₃) δ: 4.73 (dt, J=5, 10 Hz, 1H), 3.79 (s, 2H), 2.20-0.80 (m,9H), 0.89 (d, J=7 Hz, 6H), 0.79 (d, J=7 Hz, 3H).

Example 1713-(RS)-1-(2,2-Diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-oneand Single Diastereomer of1-(2,2-Diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one(HPLC second fraction)

3-(RS)-1-(2,2-Diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-onewas prepared in the same manner as in Example 71, except for usingL-menthyl bromoacetate as a reactant in place ofN-p-tolyl-2-bromoacetamide used in Example 71. The product was analyzedby high performance liquid chromatography.

HPLC Conditions:

Column: YMC-Pack CN A-514 (6.0 mm (diameter)×30 cm)

Developing solvent: hexane/isopropyl alcohol=100/1

Flow rate: 1.0 ml/min

Detection: UV 254 nm

First fraction: 53 parts (retention time=38 min)

Second fraction: 47 parts (retention time=42 min)

The diastereomeric mixture was recrystallized twice from diisopropylether to give a single diastereomer of1-(2,2-diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-oneas needles.

NMR (CDCl₃) δ: 7.33-7.18 (m, 3H), 7.18-6.91 (m, 5H), 6.87 (s, 2H), 4.76(dd, J=4.4, 5.5 Hz, 1H), 4.69 (dt, J=3.8, 10.8 Hz, 1H), 3.97 (dd, J=5.5,13.1 Hz, 1H), 3.88-3.45 (m, 5H), 2.96 (d, J=13.2 Hz, 1H), 2.51 (d,J=13.2 Hz, 1H), 2.26 (s, 3H), 1.88-0.99 (m, 9H), 1.16 (t, J=7.0 Hz, 3H),1.12 (t, J=7.4 Hz, 3H), 0.88 (d, J=6.2 Hz, 3H), 0.78 (d, J=7.4 Hz, 3H),0.70 (d, J=6.8 Hz, 3H).

The product was analyzed by high performance liquid chromatography.

HPLC Conditions:

Column: YMC-Pack CN A-514 (6.0 mm (diameter)×30 cm)

Developing solvent: hexane/isopropyl alcohol=100/1

Flow rate: 1.0 ml/min

Detection: UV 254 nm

Fraction : retention time=42 min

Example 172 Single Diastereomer of1-(2,2-Diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one(HPLC first fraction)

To a solution of 10.4 g of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in500 ml of dry tetrahydrofuran was added slowly 52.5 ml of a 0.5Msolution of lithium t-butoxide (prepared from n-butyl lithium andt-butanol) in dry tetrahydrofuran at room temperature under a nitrogenatmosphere, and the mixture was stirred at that temperature for 30minutes. To the mixture was added dropwise a solution of 8.10 g ofL-menthyl bromoacetate in 30 ml of dry tetrahydrofuran at 0° C.,followed by stirring at 0° C. for 8 hours. The reaction mixture waspoured into an aqueous solution of sodium chloride and extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand concentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1) and then recrystallized frommethanolic water to afford 7.55 g (48%) of the title compound.

HPLC Conditions:

Column: YMC-Pack CN A-514 (6.0 mm (diameter)×30 cm)

Developing solvent: hexane/isopropyl alcohol=100/1

Flow rate: 1.0 ml/min

Detection: UV 254 nm

Fraction: retention time=38 min

Rf=0.44 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.41-6.91 (m, 8H), 6.88 (s, 1H), 6.73 (s, 1H), 4.75 (dd,J=4.6, 5.7 Hz, 1H), 4.64 (dt, J=4.1, 11.1 Hz, 1H), 3.95 (dd, J=5.7, 14.6Hz, 1H), 3.89-3.45 (m, 5H), 3.03 (d, J=15.1 Hz, 1H), 2.61 (d, J=15.1 Hz,1H), 2.26 (s, 3H), 1.98-1.80 (br, 1H), 1.80-1.55 (br, 3H), 1.55-1.30(br, 1H), 1.30-0.75 (br, 4H), 1.17 (t, J=6.8 Hz, 3H), 1.11 (t, J=7.0 Hz,3H), 0.88 (d, J=6.5 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H), 0.64 (d, J=6.8 Hz,3H).

Example 173 Single Diastereomer of1-(2,2-Diethoxyethyl)-3-(D-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one(HPLC first fraction)

The title compound was prepared in the same manner as in Example 172,except for replacing L-menthyl bromoacetate used in Example 172 withD-menthyl bromoacetate.

HPLC Conditions:

Column: YMC-Pack CN A-514 (6.0 mm (diameter)×30 cm)

Developing solvent: hexane/isopropyl alcohol=100/1

Flow rate: 1.0 ml/min

Detection: UV 254 nm

Retention time: 38 min

Rf=0.44 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.41-6.91 (m, 8H), 6.88 (s, 1H), 6.73 (s, 1H), 4.75 (dd,J=4.6, 5.7 Hz, 1H), 4.64 (dt, J=4.1, 11.1 Hz, 1H), 3.95 (dd, J=5.7, 14.6Hz, 1H), 3.89-3.45 (m, 5H), 3.03 (d, J=15.1 Hz, 1H), 2.61 (d, J=15.1 Hz,1H), 2.26 (s, 3H), 1.98-1.80 (br, 1H), 1.80-1.55 (br, 3H), 1.55-1.30(br, 1H), 1.30-0.75 (br, 4H), 1.17 (t, J=6.8 Hz, 3H), 1.11 (t, J=7.0 Hz,3H), 0.88 (d, J=6.5 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H), 0.64 (d, J=6.8 Hz,3H).

Example 174(+)-1-(2,2-Diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

(1)(+)-1-(2,2-Diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 5.30 g of3-(+)-1-(2,2-diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 150 ml of methanol was added 30 ml of an aqueous solution of 1.00 gof potassium hydroxide (85%) at room temperature. The mixture wasrefluxed for 3 hours and concentrated. To the residue was added water,and the mixture was washed with chloroform. The aqueous layer wasadjusted to pH 2 with 2N hydrochloric acid and extracted with ethylacetate. The organic layer was washed with an aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and concentrated toobtain 2.8 g of the title compound.

NMR (CDCl₃) δ: 7.74 (s, 1H), 7.35-6.70 (m, 10H), 4.73 (dd, J=4.4, 5.9Hz, 1H), 4.01 (dd, J=5.9, 14.6 Hz, 1H), 3.86-3.38 (m, 5H), 2.90 (d,J=15.9 Hz, 1H), 2.65 (d, J=15.9 Hz, 1H), 2.18 (s, 3H), 1.13 (t, J=6.8Hz, 3H), 1.08 (t, J=6.8 Hz, 3H).

(2)(+)-1-(2,2-Diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

In 100 ml of dichloromethane was dissolved 2.8 g of(+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one,and 1.20 g of 4-dimethylaminopyridine, 1.90 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1.10 gof p-toluidine were successively added thereto. The mixture was stirredfor 18 hours and concentrated. The concentrate was diluted with ethylacetate, washed successively with dilute hydrochloric acid and saturatedaqueous sodium hydrogencarbonate. The organic layer was dried overanhydrous sodium sulfate, and concentrated. The crude product waspurified by silica gel column chromatography (hexane/ethyl acetate=2/1)to yield 3.90 g (81%) of the title compound as a white powder. Theresulting compound was found to be optically pure as analyzed by highperformance liquid chromatography using an optically active column(CHIRALCEL OD, produced by Daicel Chemical Industries, Ltd.).

Rf=0.21 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 8.33 (s, 1H), 7.33-6.91 (m, 14H), 4.77 (dd, J=4.4, 5.6Hz, 1H), 4.03 (dd, J=5.6, 14.1 Hz, 1H), 3.82-3.48 (m, 5H), 2.97 (d,J=14.6 Hz, 1H), 2.57 (d, J=14.6 Hz, 1H), 2.30 (s, 3H), 2.22 (s, 3H),1.16 (t, J=6.8 Hz, 3H), 1.11 (t, J=6.8 Hz, 1H).

[α]_(D) ²⁵ =27.9° (c=3.05, CHCl₃)

Example 175(-)-1-(2,2-Diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 1.26 g of a single diastereomer of1-(2,2-diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one(HPLC first fraction) in 20 ml of ethanol was added 10 ml of an aqueoussolution of 0.07 g of potassium hydroxide (85%) at room temperature, andthe mixture was stirred at 70° C. for 1 hour, followed by concentration.Water was added to the residue, and the mixture was washed withchloroform. The aqueous layer was adjusted to pH 2 by addition of 2Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and concentrated to give 0.88 gof(-)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one.The resulting product was dissolved in 50 ml of dichloromethane, and0.52 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideand 0.29 g of p-toluidine were successively added thereto. The mixturewas stirred for 18 hours and diluted with ethyl acetate, washedsuccessively with dilute hydrochloric acid and saturated aqueous sodiumhydrogencarbonate. The organic layer was dried over anhydrous sodiumsulfate, and concentrated. The resulting crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.90g (90%) of the title compound as a white powder. The resulting compoundwas found to be optically pure as analyzed by high performance liquidchromatography using an optically active column (CHIRALCEL OD, producedby Daicel Chemical Industries, Ltd.). The Rf and NMR data were equal tothose of the compound of Example 174.

[α]_(D) ²⁵ =-27.6° C. (c=1.00, CHCl₃)

EXAMPLES 176 TO 181

The following compounds were prepared in the same manner as in Example174, except for replacing p-toluidine used in Example 174 with variousamines or alcohols as a reactant.

Example 176(+)-1-(2,2-Diethoxyethyl)-3-(4-iodophenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

NMR (CDCl₃) δ: 8.60 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.32-6.94 (m, 11H),6.84 (s, 1H), 4.77 (dd, J=4.4, 6.3 Hz, 1H), 4.00 (dd, J=6.3, 10.4 Hz,1H), 3.82-3.46 (m, 5H), 2.96 (d, J=14.8 Hz, 1H), 2.65 (d, J=14.8 Hz,1H), 2.23 (s, 3H), 1.20-1.07 (m, 6H).

Example 177(+)-1-(2,2-Diethoxyethyl)-3-(2-bromoethoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

Rf=0.14 (n-hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.31-7.22 (m, 2H), 7.16-6.98 (m, 6H), 6.61 (s, 1H), 6.52(s, 1H), 4.73 (dd, J=4.9, 5.9 Hz, 1H), 4.38 (t, J=6.3 Hz, 2H), 3.97 (dd,J=5.9, 8.3 Hz, 1H), 3.84-3.51 (m, 5H), 3.42 (t, J=6.3 Hz, 2H), 2.28 (s,3H), 1.17 (t, J=7.3 Hz, 3H), 1.13 (t, J=7.8 Hz, 3H).

MS (m/e): 563, 561 (M⁺), 517, 515, 438, 158, 103

Example 178(+)-1-(2,2-Diethoxyethyl)-3-(2-iodoethoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

Rf=0.14 (n-hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 7.31-6.98 (m, 8H), 6.50 (s, 2H), 4.75 (dd, J=4.9, 5.8 Hz,1H), 4.34 (dt, J=1.5, 6.9 Hz, 2H), 3.96 (dd, J=5.8H, 14.2 Hz, 1H),3.85-3.52 (m, 5H), 3.19 (t, J=6.9 Hz, 2H), 2.93 (d, J=15.1 Hz, 1H), 2.64(d, J=15.1 Hz, 1H), 2.29 (s, 3H), 1.17 (t, J=7.3 Hz, 3H), 1.13 (t, J=7.3Hz, 3H).

MS (m/e): 609 (M⁺), 563, 535, 414, 103

[α]_(D) ²⁵ =+8.6° (c=1.00, CHCl₃)

Example 179(+)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-(5-methylpyrido-2-yl)aminocarbonylmethyl)indolin-2-one

The NMR data were equal to those of the compound of Example 138.

[α]_(D) ²⁵ =+53.76° (c=1.09, CHCl₃)

Example 180(+)-1-(2,2-Diethoxyethyl)-3-((4-(N,N-dimethylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The NMR data were equal to those of the compound of Example 130.

[α]_(D) ²⁵ =+55.09° (c=1.02, CHCl₃)

Example 181(+)-1-(2,2-Diethoxyethyl)-3-((2-methoxypyrido-5-yl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The NMR data were equal to those of the compound of Example 143.

[α]_(D) ²⁵ =+22.54° (c=1.02, CHCl₃)

EXAMPLES 182 TO 184

The following compounds were prepared in the same manner as in Example175, except for using various amines as a reactant in place ofp-toluidine used in Example 175.

Example 182(-)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-((5-methylpyrido-2-yl)aminocarbonylmethyl)indolin-2-one

The NMR data were equal to those of the compound of Example 138.

[α]_(D) ²⁵ =-58.83° (c=1.03, CHCl₃)

Example 183(-)-1-(2,2-Diethoxyethyl)-3-((4-(N,N-dimethylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The NMR data were equal to those of the compound of Example 130.

[α]_(D) ²⁵ =-60.91° (c=1.06, CHCl₃)

Example 184(-)-1-(2,2-Diethoxyethyl)-3-((2-methoxypyrido-5-yl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The NMR data were equal to those of the compound of Example 143.

[α]_(D) ²⁵ =-25.19° (c=1.04, CHCl₃)

Example 185(3RS)-1-(2,2-Diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

To a solution of 0.207 g of(RS)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-onein 4 ml of dry dimethyl sulfoxide was added 0.5 ml of a 1M solution ofpotassium t-butoxide in dry dimethyl sulfoxide at room temperature undera nitrogen atmosphere. After stirring the mixture for 30 minutes, asolution of 0.166 g of L-menthyl bromoacetate in 2 ml of dry dimethylsulfoxide was added thereto dropwise, followed by stirring at thattemperature for 30 minutes. The reaction mixture was poured into anaqueous solution of sodium chloride and extracted with ethyl ether. Theethyl ether layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1) to give 0.170 g (56%) of thetitle compound. As a result of analysis by high performance liquidchromatography, the product was found to consist of both diastereomersat a ratio of approximately 1:1.

HPLC Conditions:

Column: YMC-Pack CN A-514 (6.0 mm (diameter)×30 cm)

Developing solvent: hexane/isopropyl alcohol=100/1

Flow rate: 1.0 ml/min

Detection: UV 254 nm

Fractions: 56 parts (retention time=47 min) 44 parts (retention time=52min)

Rf=0.36 (hexane/ethyl acetate=2/1)

NMR (CHCl₃) δ: 7.30-7.20 (m, 2H), 7.16-6.92 (m, 5H), 6.79-6.75 (m, 2H),6.57-6.52 (m, 1H), 4.80-4.75 (m, 1H), 4.72-4.62 (m, 1H), 3.99-3.51 (m,6H), 3.71 (s, 3H), 3.01 (d, J=14.8 Hz, 0.5H), 2.96 (d, J=15.2 Hz, 0.5H),2.62 (d, J=15.2 Hz, 0.5H), 2.54 (d, J=14.8 Hz, 0.5H), 1.83-1.71 (br,1H), 1.65-1.59 (m, 4H), 1.42-0.57 (m, 3H), 1.21-1.09 (m, 6H), 0.89 (d,J=6.9 Hz, 1.5H), 0.88 (d, J=6.9 Hz, 1.5H), 0.82 (d, J=6.9 Hz, 1.5H),0.77 (d, J=6.9 Hz, 1.5H), 0.70 (d, J=6.9 Hz, 1.5H), 0.64 (d, J=6.9 Hz,1.5H).

Example 186 Single Diastereomer of1-(2,2-Diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one(HPLC first fraction)

The same procedure of Example 172 was repeated except for using(RS)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-oneas a starting material. The crude product was recrystallized fromisopropyl ether to obtain the title compound as needles in a 32% yield.As a result of high performance liquid chromatography analysis, theproduct was confirmed to consist of a single diastereomer.

HPLC Conditions:

Column: YMC-Pack CN A-514 (6.0 mm (diameter)×30 cm)

Developing solvent: hexane/isopropyl alcohol=100/1

Flow rate: 1.0 ml/min

Detection: UV 254 nm

Retention time: 47 min

Rf=0.36 (hexane/ethyl acetate=2/1)

NMR (CHCl₃) δ: 7.29-7.24 (m, 2H), 7.15-7.09 (m, 2H), 6.70 (t, J=7.6 Hz,1H), 6.95-6.91 (m, 2H), 6.79-6.73 (m, 2H), 6.53 (dd, J=2.0, 8.2 Hz, 1H),4.77 (dd, J=5.3, 5.9 Hz, 1H), 4.75-4.61 (m, 1H), 3.93 (dd, J=5.9, 15.9Hz, 1H), 3.85 (dd, J=5.3, 15.9 Hz, 1H), 3.73-3.54 (m, 4H), 3.70 (s, 3H),1.91 (br, 1H), 1.87 (br, 1H), 1.67 (m, 4H), 1.36-0.71 (m, 3H), 1.19 (t,J=6.9 Hz, 3H), 1.11 (t, J=6.9 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H), 0.83 (d,J=7.3 Hz, 1H), 0.66 (d, J=7.0 Hz, 3H).

Example 187 Single Diastereomer of1-(2,2-Diethoxyethyl)-3-(D-menthoxy)carbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one(HPLC first fraction)

The same procedure as in Example 172 was repeated, except for using(RS)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-oneas a starting material and replacing L-menthyl bromoacetate as areactant with D-menthyl bromoacetate. Recrystallization of the crudeproduct from isopropyl ether gave the title compound as needles in a 32%yield. As a result of high performance liquid chromatography analysis,the compound was confirmed to consist of a single diastereomer. Becausethe compound is an enantiomer of the compound of Example 186, the HPLCand NMR data are the same as those of the latter compound.

Example 188(+)-1-(2,2-Diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

To a solution of 2.57 g of a single diastereomer of1-(2,2-diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one(HPLC first fraction) in 150 ml of ethanol was added 50 ml of an aqueoussolution of 0.60 g of potassium hydroxide (85%) at room temperature. Themixture was heated under reflux for 1 hour, followed by concentration.Water was added to the residue, and the mixture was washed withchloroform. The aqueous layer was adjusted to pH 2 with 2N hydrochloricacid, and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and concentrated to yield 1.90 g of(+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one.

In 30 ml of dichloromethane was dissolved 0.5 g of(+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one,and 0.22 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and 0.20 g of p-toluidine were successively added thereto.After stirring the mixture for 9 hours, the reaction mixture was dilutedwith ethyl acetate and washed successively with dilute hydrochloric acidand saturated aqueous sodium hydrogencarbonate. The organic layer wasdried over anhydrous sodium sulfate and concentrated. The crude productwas purified by silica gel column chromatography (hexane/ethylacetate=2/1) to yield 0.49 g of the title compound as a white powder.

Rf=0.21 (hexane/ethyl acetate=2/1)

NMR (CDCl₃) δ: 8.15 (s, 1H), 7.35-7.23 (m, 6H), 7.13-6.91 (m, 6H), 6.73(d, J=7.3 Hz, 1H), 6.50 (dd, J=2.4, 7.8 Hz, 1H), 4.79 (dd, J=4.4, 5.9Hz, 1H), 3.98 (dd, J=5.9, 14.1 Hz, 1H), 3.86-3.52 (m, 5H), 3.67 (s, 3H),2.98 (d, J=14.6 Hz, 1H), 2.54 (d, J=14.6 Hz, 1H), 2.30 (s, 3H), 1.18 (t,J=6.8 Hz, 3H), 1.10 (t, J=6.8 Hz, 3H).

[α]_(D) ²⁵ =+33.8° (c=1.07, CHCl₃)

Example 189(-)-1-(2,2-Diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one

To a solution of 1.89 g of a single diastereomer of1-(2,2-diethoxyethyl)-3-(D-menthoxy)carbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one(HPLC first fraction) in 100 ml of ethanol was added 30 ml of an aqueoussolution of 0.46 g of potassium hydroxide (85%) at room temperature, andthe mixture was stirred at 80° C. for 2 hours followed by concentration.Water was added to the concentrate, and the mixture was washed withchloroform. The aqueous layer was adjusted to pH 2 by addition of 2Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and concentrated to afford 1.76g of(-)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one.

In 30 ml of dichloromethane was dissolved 0.50 g of(-)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one,and 0.22 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride and 0.20 g of p-toluidine were successively added thereto.After stirring the mixture for 9 hours, the reaction mixture was dilutedwith ethyl acetate and washed successively with dilute hydrochloric acidand saturated aqueous sodium hydrogencarbonate. The organic layer wasdried over anhydrous sodium sulfate and concentrated. The crude productwas purified by silica gel column chromatography (hexane/ethylacetate=2/1) to give 0.46 g of the title compound as a white powder.Because the compound is an enantiomer of the compound of Example 188,the NMR data are the same as those of the latter compound.

[α]_(D) ²⁵ =-36.9° (c=1.02, CHCl₃)

EXAMPLES 190 TO 191

The following compounds were prepared in the same manner as in Example188, except for using various amines as a reactant in place ofp-toluidine used in Example 188.

Example 190(+)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((5-methylpyrido-2-yl)aminocarbonylmethyl)indolin-2-one

The Rf and NMR data were equal to those of the compound of Example 158.

[α]_(D) ²⁵ =+54.08° (c=1.03, CHCl₃)

Example 191(+)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-(N'N-dimethylaminophenyl)aminocarbonylmethyl)indolin-2-one

The Rf and NMR data were equal to those of the compound of Example 156.

[α]_(D) ²⁵ =+61.79° (c=1.00, CHCl₃)

EXAMPLES 192 TO 193

The following compounds were prepared in the same manner as in Example189, except for using various amines as a reactant in place ofp-toluidine used in Example 189.

Example 192(-)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((5-methylpyrido-2-yl)aminocarbonylmethyl)indolin-2-one

The Rf and NMR data were equal to those of the compound of Example 158.

[α]_(D) ²⁵ =-54.91° (c=1.01, CHCl₃)

Example 193(-)-1-(2,2-Diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-N'N-dimethylamino)phenyl)aminocarbonylmethyl)indolin-2-one

The Rf and NMR data were equal to those of the compound of Example 156.

[α]_(D) ²⁵ =-63.99° (c=1.00, CHCl₃)

Example 194(+)-1-(2,2-Diethoxyethyl)-3-((4-(N,N-dimethylamino)phenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-onePotassium Hydrogensulfate

The compound obtained in Example 180 was mixed with 1 equivalent ofpotassium hydrogensulfate, and the mixture was recrystallized frommethanol to obtain the title compound as needles.

Melting point: 180° C. (decomposition)

NMR (DMSO-d₆) δ: 9.98 (br, 1H), 9.13 (s, 1H), 7.57 (s, 1H), 7.46 (d,J=8.2 Hz, 2H), 7.25-6.80 (m, 11H), 4.75-4.69 (m, 1H), 3.85 (dd, J=5.8,14.6 Hz, 1H), 3.77-3.44 (m, 5H), 2.83 (d, J=14.1 Hz, 1H), 2.51 (s, 6H),2.47 (d, J=14.1 Hz, 1H), 2.18 (s, 3H), 1.11 (t, J=7.3 Hz, 3H), 1.07 (t,J=6.8 Hz, 3H).

[α]_(D) ²⁴ +98.88° (c=0.72, MeOH).

REFERENCE EXAMPLE 27 1-(2,2-Diethoxyethyl)indole

To a solution of 12 g of indole in 100 ml of dimethyl sulfoxide wasadded 6.5 g of sodium hydride at room temperature. The mixture wasstirred at the same temperature for 1 hour, and 20 ml ofbromoacetaldehyde diethyl acetal was added thereto, followed by furtherstirring at 50° C. for 1 hour. After cooling, the reaction mixture waspoured into water, and the product was extracted with ethyl ether. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated to give 23 g of the title compound.

NMR (CDCl₃) δ: 7.60 (d, J=6.9 Hz, 1H), 7.39 (d, J=9.1 Hz, 1H), 7.26-7.03(m, 3H), 6.48 (d, J=3.4 Hz, 1H), 4.64 (t, J=5.1 Hz, 1H), 4.20 (d, J=5.1Hz, 2H), 3.79-3.47 (m, 2H), 3.42-3.24 (m, 2H), 1.12 (t, J=7.3 Hz, 6H).

REFERENCE EXAMPLE 28 1-(2,2-Diethoxyethyl)-3,3-dichloroindolin-2-one

To a suspension of 23 g of 1-(2,2-diethoxyethyl)indole and 31 g ofpotassium dihydrogenphosphate in 1 l of ethyl acetate was added 700 mlof a 5% aqueous solution of sodium hypochlorite under ice-cooling,followed by stirring at that temperature for 10 minutes. The mixture waswashed successively with water and an aqueous solution of potassiumcarbonate. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give 31 g of the title compound.

Rf=0.50 (hexane/ethyl acetate=3/1)

NMR (CDCl₃) δ: 7.61 (d, J=8.2 Hz, 1H), 7.40-7.30 (m, 1H), 7.22-6.98 (m,2H), 4.74 (t, J=5.4 Hz, 1H), 3.84 (d, J=5.4 Hz, 2H), 3.86-3.67 (m, 2H),3.60-3.40 (m, 2H), 1.14 (t, J=7.3 Hz, 6H).

REFERENCE EXAMPLE 29 1-(2,2-Diethoxyethyl)isatin

To a solution of 31 g of 1-(2,2-diethoxyethyl)-3,3-dichloroindolin-2-onein 200 ml of dimethyl sulfoxide was added dropwise 50 ml of an aqueoussolution of 14.5 g of sodium hydroxide in such a manner that thereaction temperature might not exceed 20° C., followed by stirring atthe same temperature for 45 minutes. To the mixture was slowly added15.5 ml of concentrated hydrochloric acid, followed by stirring at roomtemperature for 1.5 hours. Ethyl acetate was added to the reactionmixture, and the mixture was washed successively with water and anaqueous solution of sodium hydrogencarbonate. The organic layer wasdried over anhydrous sodium sulfate and concentrated to give 25 g of thetitle compound.

Rf=0.83 (chloroform/methanol=20/1)

NMR (CDCl₃) δ: 7.75-6.95 (m, 4H), 4.71 (t, J=5 Hz, 1H), 3.89-3.40 (m,6H), 1.16 (t, J=7 Hz, 6H).

Example 195(RS)-1-(2,2-Ethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

In 3.8 l of methanol was dissolved 176 g of isatin while heating, and asolution of 100 g of O-methylhydroxylamine hydrochloride and 136 g ofsodium acetate trihydrate in 400 ml of water was added thereto. Theresulting mixture was stirred at room temperature for 10 minutes,followed by concentration. Water was added to the residue, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium hydrogencarbonate, dried over anhydroussodium sulfate, and concentrated to give 192 g (91%) of3-methoxyiminoindolin-2-one. The resulting crude product was used in thesubsequent reaction without being purified.

NMR (CDCl₃) δ: 9.36 (br, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.34 (dt, J=1.3,7.6 Hz, 1H), 7.05 (dt, J=1.0, 7.6 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 4.31(s, 3H).

To a suspension of sodium hydride (prepared by washing 50 g of 60% oilysodium hydride with hexane) in 1 l of N,N-dimethylformamide was addeddropwise a solution of 176 g of 3-methoxyiminoindolin-2-one in 3 l ofN,N-dimethylformamide at 0° C. in a nitrogen stream. To the mixture wereadded 1 l of N,N-dimethylformamide and 330 ml of bromoacetaldehydediethyl acetal, and the mixture was heated to 70° C., at which it wasstirred for 45 hours. The reaction mixture was concentrated, and theconcentrate was diluted with ethyl acetate and washed with an aqueoussolution of sodium chloride. The organic layer was dried over anhydroussodium sulfate and concentrated to give 284 g (97%) of1-(2,2-diethoxyethyl)-3-methoxyiminoindolin-2-one.

NMR (CDCl₃) δ: 7.93 (d, J=7.8 Hz, 1H), 7.36 (dt, J=1.5, 7.8 Hz, 1H),7.08-7.00 (m, 2H), 4.70 (t, J=5.4 Hz, 1H), 4.29 (s, 3H), 3.85 (d, J=5.4Hz, 2H), 3.79-3.43 (m, 4H), 1.14 (t, J=7.3 Hz, 6H).

To a solution of 0.51 g of1-(2,2-diethoxyethyl)-3-methoxyiminoindolin-2-one in 30 ml of ethanolwere added 50 mg of 5% Pd/C and 1 ml of 2N hydrochloric acid, and theresulting suspension was stirred at room temperature for 18 hours undera hydrogen atmosphere. The reaction mixture was filtered through Cerite,and the filtrate was concentrated. The residue was suspended in 30 ml oftoluene, and 0.25 ml of triethylamine and 0.27 ml of p-tolyl isocyanatewere added thereto, followed by stirring at room temperature for 1 hour.The reaction mixture was concentrated and washed with water to give 0.55g of the title compound.

NMR (DMSO-d₆) δ: 8.63 (s, 1H), 7.33-7.16 (m, 4H), 7.12-7.16 (m, 4H),5.05 (d, J=7.4 Hz, 1H), 4.77-4.63 (m, 1H), 3.84 (dd, J=5.7, 14.6 Hz,1H), 3.77-3.40 (m, 5H), 2.22 (s, 3H), 1.08 (t, J=7.4 Hz, 3H), 1.06 (t,J=7.4 Hz, 3H).

Example 196(+)-3-(p-Bromobenzyloxy)carbonylmethyl-1-(2,2-diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one

In 10 ml of dimethyl sulfoxide was dissolved 0.336 g of(+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one.To the solution were added successively 0.108 g of4-dimethylaminopyridine, 0.170 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.166 gof 4-bromobenzyl alcohol. The resulting mixture was stirred for 18hours, followed by concentration. The concentrate was diluted with ethylether, washed successively with dilute hydrochloric acid and a saturatedaqueous solution of sodium hydrogencarbonate. The organic layer wasdried over anhydrous sodium sulfate, and concentrated. The crude productwas purified by silica gel column chromatography (hexane/ethylacetate=2/1) to give 0.219 g (48%) of the title compound as a whitepowder.

NMR (CDCl₃) δ: 7.45 (d, J=8.8 Hz, 2H), 7.30-6.80 (m, 10H), 6.71 (s, 1H),6.60 (s, 1H), 5.05 (d, J=12.7 Hz, 1H), 5.00 (d, J=12.7 Hz, 1H), 4.73(dd, J=4.9, 5.9 Hz, 1H), 3.93 (dd, J=5.9, 14.6 Hz, 1H), 3.83-3.30 (m,5H), 2.97 (d, J=15.1 Hz, 1H), 2.65 (d, J=15.1 Hz, 1H), 2.28 (s, 3H),1.15 (t, J=7.3 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).

Example 1973-(+)-1-(2,2-Diethoxyethyl)-3-(N'-(4-methylphenyl)ureido)-3-((1R-1-methylpropoxy)carbonylmethyl)indolin-2-one

The title compound was prepared in the same manner as in Example 196,except for using R-2-butanol as a reactant in place of 4-bromobenzylalcohol used in Example 196.

NMR (CDCl₃) δ: 7.30-7.20 (m, 2H), 7.13-6.92 (m, 6H), 6.89 (s, 1H), 6.79(s, 1H), 4.87-4.70 (m, 2H), 3.95 (dd, J=5.9, 14.1 Hz, 1H), 3.86-3.46 (m,5H), 2.95 (d, J=15.1 Hz, 1H), 2.56 (d, J=15.1 z, 1H), 2.26 (s, 3H),1.55-1.37 (m, 2H), 1.21-1.00 (m, 9H), 0.81 (t, J=8.1 Hz, 3H).

Example 198(+)-1-Formylmethyl-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

To a solution of 0.227 g of(+)-1-(2,2-diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-onein 5 ml of acetone was added 5 ml of 6N hydrochloric acid, followed byheating under reflux for 10 minutes. The reaction mixture wasconcentrated, and the residue was diluted with ethyl acetate and washedtwice with an aqueous solution of sodium chloride. The organic layer wasdried over anhydrous magnesium sulfate and concentrated to give 0.189 gof the title compound as a crude product.

NMR (CDCl₃) δ: 9.59 (s, 1H), 8.12 (s, 1H), 7.42 (s, 1H), 7.31-6.84 (m,12H), 6.57 (d, J=7.6 Hz, 1H), 4.62 (d, J=18.8 Hz, 1H), 4.29 (d, J=18.8Hz, 1H), 2.90 (d, J=15.9 Hz, 1H), 2.58 (d, J=15.9 Hz, 1H), 2.25 (s, 3H),2.18 (s, 3H).

Example 199(+)-1-Formylmethyl-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 198,except for starting with(+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-onein place of(+)-1-(2,2-diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 198.

NMR (DMSO-d₆) δ: 9.61 (s, 1H), 8.95 (s, 1H), 7.33-6.94 (m, 10H), 4.68(d, J=18.5 Hz, 1H), 4.54 (d, J=18.5 Hz, 1H), 2.87 (d, J=15.8 Hz, 1H),2.56 (d, J=15.8 Hz, 1H), 2.17 (s, 3H).

Example 2003-(+)-1-Formylmethyl-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

The title compound was prepared in the same manner as in Example 198,except for starting with(+)-1-(2,2-diethoxyethyl)-3-(L-menthoxy)carbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-onein place of(+)-1-(2,2-diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-oneused in Example 198.

NMR (CDCl₃) δ: 9.72 (s, 1H), 7.33-6.68 (m, 10H), 4.75-4.61 (m, 2H), 4.47(d, J=17.8 Hz, 1H), 2.99 (d, J=15.4 Hz, 1H), 2.63 (d, J=15.4 Hz, 1H),2.26 (s, 3H), 1.92-1.84 (br, 1H), 1.71-1.59 (br, 3H), 1.43-1.38 (br,1H), 1.30-1.14 (br, 4H), 0.89 (d, J=6.6 Hz, 3H), 0.82 (d, J=6.9 Hz, 3H),0.64 (d, J=6.9 Hz, 3H).

Example 201(+)-1-(2-Hydroxyiminoethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one

In 1 ml of methanol was dissolved 0.050 g of(+)-1-formylmethyl-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one,and a solution of 0.021 g of hydroxylamine hydrochloride and 0.021 g ofsodium acetate in 1 ml of water was added thereto. The resulting mixturewas stirred at room temperature for 1 hour and concentrated. Water wasadded to the residue, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodiumhydrogencarbonate, dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography (dichloromethane/ethyl acetate=1/1) to give 0.045 g ofthe title compound.

Rf=0.18 (dichloromethane/ethyl acetate=2/1)

NMR (CDCl₃ -DMSO-d₆) δ: 10.09 (br, 0.5H), 9.62 (br, 0.5H), 8.69 (br,0.5H), 7.57 (br, 0.5H), 7.43-7.38 (m, 1H), 7.30-7.14 (m, 5H), 7.06-6.77(m, 9H), 4.71-4.52 (m, 1.5H), 4.30-4.18 (m, 0.5H), 2.89 (d, J=14.5 Hz,0.5H), 2.85 (d, J=14.5 Hz, 0.5H), 2.51-2.40 (m, 1H), 2.26 (s, 3H), 2.19(s, 3H).

Structural formulae of the compounds prepared in the foregoing Examplesare shown in Tables A and B below.

TEST EXAMPLE 1 Gastrin Receptor Binding Test in Guinea Pig GastricGlands Preparation of Gastric Glands

Guinea pig gastric glands were prepared according to the method ofChang, et al., Biochem. Biophys. Res. Commun., 134, 895 (1986). Thegastric mucosa of a Hartley male guinea pig was peeled off. Afterwashing, the mucosa was minced with scissors in buffer A (Eagle's MEMcontaining 2 mM L-glutamine and 25 mM HEPES; pH 7.4). After washing, theminced tissue was incubated in buffer A containing 0.025% collagenase,0.01% soy bean trypsin inhibitor, and 0.1% BSA at 37° C. for 60 minutesunder 95% 02 and 5% CO₂. The gastric glands were isolated from thetissue with a pipette, washed twice with buffer A, and filtered througha mesh. Then, the gastric glands were obtained by centrifugation.

Binding Test

Guinea pig gastric glands were resuspended in buffer B (Hank's solutioncontaining 10 mM HEPES and 0.2% BSA; pH 7.4) (10 ml of buffer B perguinea pig).

To 200 μl of the suspension containing the resuspended isolated gastricglands were added 20 pl of ¹²⁵ I-gastrin I human (final concentration:22.5 pM). Then, 10 μl of a test compound or a solvent (for totalbinding) or 10 μM Pentagastrin (for nonspecific binding), and buffer Bwas added there to make a total volume of 1 ml. The reaction mixture wasincubated at 25° C. for 45 minutes and then centrifuged at 12000 g. Thesupernatant was removed by suction, and the radioactivity of theisolated gastric glands was measured with a gamma-counter.

The specific binding of gastrin to gastrin receptors was obtained from adifference between the total binding and the nonspecific binding. TheIC₅₀ of the test compound in inhibition of specific binding wascalculated.

The results obtained are shown in Table C.

TEST EXAMPLE 2 Inhibitory Activity on Gastric Acid Secretion in PyrolusLigated Rats

Sprague-Dawley male rats weighing about 200 g were deprived of food for24 hours while allowed water ad libitum. The abdomen was opened underanesthesia with ethyl ether, the pyrolus ligated, and the abdomenclosed. The rats were deprived of food and water for 4 hours until theywere surcrified with ethyl ether. The stomach was removed, and gastricjuice was collected and measured. The gastric juice was centrifuged at3000 rpm, and the supernatant was titrated up to pH 7.0 with 0.1N NaOHsolution to obtain the acidity of the gastric juice. The amount of thegastric acid output was calculated by multiplying the gastric juicevolume by the acidity, and the percent inhibition of acid secretion wasobtained according to the following equation. A test compound, suspendedin a 3% gum arabic solution, was administered intraduodenally at a doseof 2 ml/kg immediately after the pyrolus ligation.

    Inhibition (%)=[(Average amount of gastric acid output in control group-Average amount of gastric acid output in test group)/Average amount of gastric acid secreted in test group]×100

The results obtained are shown in Table C.

TEST EXAMPLE 3 CCK-B Receptor Binding Test in Rat Cerebral Cortex

A rat cortical membrane fraction was prepared in accordance with themethod of Chang, et al., Proc. Natl. Acad. Sci., U.S.A., 83, 4923(1986). Sprague-Dawley male rats were sucrified and the brains wereremoved and immersed in a 50 mM Tris-HCl buffer (pH 7.4) underice-cooling, and the cortex was dissected. Cerebral cortex was minced inthe same buffer, and homogenized with Polytron. The homogenate wascentrifuged at 2,500 g, and the supernatant was further centrifuged at50,000 g. The pellet was resuspended in a reaction buffer solution (10mM HEPES, 5 mM MgCl₂, 1 mM EGTA, 130 mM NaCl; pH 6.5).

Binding Test

To 150 μl of the resulting rat cerebral cortex suspension were added 20μl of ¹²⁵ 1-CCK-8 sulfated (final concentration: 15 pM) and 10 μl of atest compound or a solvent (for total binding) or 1 pM CCK-8 sulfated(for nonspecific binding), and the reaction buffer solution was addedthere to make 1 ml. The reaction mixture was incubated at 25° C. for 120minutes, followed by filtration through a GF/B filter (produced byWhatman). The radioactivity of the membrane fraction adsorbed onto thefilter was measured with a gamma-counter.

The specific binding to CCK-B receptors was obtained from a differencebetween the total binding and the nonspecific binding. The IC₅₀ of thetest compound in inhibition of specific binding was calculated.

The results obtained are shown in Table D.

As is apparent from Table C, it was confirmed that the compound of thepresent invention exhibits excellent gastrin receptor antagonism as wellas inhibitory effect on gastric acid secretion.

As is apparent from Table D, it was confirmed that the compound of thepresent invention exhibits excellent antagonism against CCK-B receptors.

                                      TABLE A-1                                   __________________________________________________________________________      #STR14##                                                                       -                                                                          Ex. No.                                                                           (R.sub.1)n                                                                        R.sub.2    X  R.sub.3      Y  R.sub.4                                 __________________________________________________________________________       1 --                                                                                                               NH R15##                                                                      NH R16##                                                                      #STR17##                                 -  2 5-NO.sub.2 H " " " "                                                     3 -- --CH.sub.2 CH═CH.sub.2 " " " "                                       -  4 --                                                                                                            " " " "                                  -  5 -- --CH.sub.2 CH(OCH.sub.3).sub.2 " " " "                                6 -- --CH.sub.2 CH(OC.sub.3 H.sub.7 -n).sub.2 " " " "                         -  7 --                                                                                                            " " " "                                  -  8 -- H " " " "                                                             -  9 -- H "                                                                                                        " TR20##                                                                      #STR21##                                 - 10 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 "                                                                    " TR22##                                                                      #STR23##                                 - 11 -- " "                                                                                                        " TR24##                                                                      #STR25##                                 - 12 -- " "                                                                                                        " TR26##                                                                      #STR27##                                 - 13 -- " "                                                                                                        " TR28##                                                                      #STR29##                                 - 14 -- " "                                                                                                        " TR30##                                                                      #STR31##                                 - 15 -- " "                                                                                                        " TR32##                                                                      #STR33##                                 - 16 -- " "                                                                                                        " TR34##                                                                      #STR35##                                 - 17 -- " "                                                                                                        " TR36##                                                                      #STR37##                                 - 18 -- " "                                                                                                        " TR38##                                                                      #STR39##                                 - 19 -- " "                                                                                                        " TR40##                                                                      #STR41##                                 - 20 -- " "                                                                                                        " TR42##                                                                     ##STR43##                              __________________________________________________________________________

                                      TABLE A-2                                   __________________________________________________________________________      #STR44##                                                                    Ex. No.                                                                           (R.sub.1)n                                                                       R.sub.2      X  R.sub.3    Y  R.sub.4                                  __________________________________________________________________________      21 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 NH                                                                     NH R45##                                                                      #STR46##                                  - 22 -- H CH.sub.2                                                                                                CH.sub.2                                                                      #STR48##                                  - 23 --                                                                                                           " " " "                                   - 24 -- CH.sub.3 " " " "                                                      - 25 --                                                                                                           " " " "                                   - 26 --                                                                                                           " " " "                                   - 27 --                                                                                                           O " " "                                   -  53a -- --CH.sub.2 COOC.sub.2 H.sub.5 NH " " OC.sub.2 H.sub.5                                                   53b -- H " " " "                          -  54a --                                                                                                         " " " ##                                                                      #STR54##                                  -  54b -- H " " " "                                                          55 -- " " " " OH                                                              56 -- --CH.sub.2 COOH " " " "                                                  - 57 -- H " " "                                                                                                   #STR55##                                  - 58 -- " " " "                                                                                                   #STR56##                                  - 59 -- " " " "                                                                                                   #STR57##                                  - 60 -- " CH.sub.2 " NH                                                                                           #STR58##                                  - 61 --                                                                                                           " " " CH.sub.3                            - 62 -- " " " "                                                                                                   #STR60##                                  - 63 --                                                                                                           NH " CH.sub.2 "                        __________________________________________________________________________

                                      TABLE A-3                                   __________________________________________________________________________      #STR62##                                                                       -                                                                          Ex. No.                                                                           (R.sub.1)n                                                                        R.sub.2      X  R.sub.3     Y  R.sub.4                                __________________________________________________________________________      64 -- --CH.sub.2 COOC.sub.2 H.sub.5 NH                                                                               CH.sub.2                                                                      #STR64##                                - 65 --                                                                                                             " " " "                                 - 66 --                                                                                                             " " " "                                 - 67 -- CH.sub.3 " " " "                                                      - 68 --                                                                                                             " " " "                                 - 69 -- --CH.sub.2 OCH.sub.3 " " " "                                         70 -- --CH.sub.2 CH(C.sub.3 H.sub.7 -n).sub.2 " " " "                         71 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 " " " "                           72 7-CH.sub.3 H " " " "                                                        - 73 --                                                                                                             " " " "                                 - 74 5-CH.sub.3 --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 " " " "                75 5-F " " " " "                                                              76 5-OCH.sub.3 " " " " "                                                      77 5-Br " " " " "                                                              - 78 -- " "                                                                                                         " " 69##                                - 79 -- " "                                                                                                         " " 70##                                - 80 -- " "                                                                                                         " " 71##                                - 81 -- " "                                                                                                         " " 72##                                - 82 -- " "                                                                                                         " " 73##                                - 83 -- " "                                                                                                         " "R74##                             __________________________________________________________________________

                                      TABLE A-4                                   __________________________________________________________________________      #STR75##                                                                       -                                                                          Ex. No.                                                                           (R.sub.1)n                                                                       R.sub.2          X   R.sub.3        Y   R.sub.4                        __________________________________________________________________________      84 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 NH                                                                               CH.sub.2                                                                      #STR77##                        - 85 -- " "                                                                                                                 " " 78##                        - 86 -- " " C.sub.2 H.sub.5 " "                                               - 87 -- " "                                                                                                                 " " 79##                        - 88 -- " "                                                                                                                 " " 80##                        - 89 -- " "                                                                                                                 " " 81##                        - 90 -- " "                                                                                                                 " " 82##                        - 91 -- " "                                                                                                                 " " 83##                        - 92 -- " "                                                                                                                 " " 84##                        - 93 -- " "                                                                                                                 " " 85##                        - 94 -- " "                                                                                                                 " " 86##                        - 95 -- " "                                                                                                                 " " 87##                        - 96 -- --CH.sub.2 CH(OC.sub.3 H.sub.7 -n).sub.2 "                                                                          " " 88##                        - 97 -- --CH.sub.2 CHO " " " "                                                - 98 --                                                                                                                     " " " "                         - 99 --                                                                                                                     " " " "                         - 100  -- --CH.sub.2 CH(OCH.sub.3).sub.2 " " " "                              - 101  --                                                                                                                   " " " "                         - 102  -- --CH.sub.2 CH.sub.2 NHCH.sub.3.NCl " " " "                          - 103  --                                                                                                                   " " " "#                     __________________________________________________________________________

                                      TABLE A-5                                   __________________________________________________________________________      #STR93##                                                                       -                                                                          Ex. No.                                                                           (R.sub.1)n                                                                       R.sub.2  X  R.sub.3    Y  R.sub.4                                      __________________________________________________________________________      104 -- --CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 NH                                                                CH.sub.2                                                                      #STR95##                                      - 105 -- --CH.sub.2 CH(SCH.sub.3).sub.2 " " " "                              106 -- --CH.sub.2 CH(SC.sub.2 H.sub.5).sub.2 " " " "                          107 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 " " " OC.sub.2 H.sub.5                                           108 -- " " " " OH                              - 109 -- " " " "                                                                                              #STR96##                                      - 110 -- " " " "                                                                                              #STR97##                                      - 111 -- " " " "                                                                                              #STR98##                                      - 112 -- " " " "                                                                                              #STR99##                                      - 113 -- " " " " --NHC.sub.3 H.sub.7 -n                                       - 114 -- " " " "                                                                                              #STR100##                                     - 115 -- " " " "                                                                                              #STR101##                                     - 116 -- " " " " --NH(CH.sub.2).sub.3 COOC.sub.2 H.sub.5                     117 -- " " " " --NHOCH.sub.3                                                   - 118 -- " " " "                                                                                              #STR102##                                     - 119 -- " " " " --NHCH.sub.2 CH(OC.sub.2 H.sub.5).sub.2                      - 120 -- " " " "                                                                                              #STR103##                                     - 121 -- " " " "                                                                                              #STR104##                                     - 122 -- " " " "                                                                                              #STR105##                                     - 123 -- " " " "                                                                                             ##STR106##                                  __________________________________________________________________________

                                      TABLE A-6                                   __________________________________________________________________________      #STR107##                                                                   Ex. No.                                                                           (R.sub.1)n                                                                       R.sub.2  X  R.sub.3      Y  R.sub.4                                    __________________________________________________________________________      124 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 NH                                                                  CH.sub.2                                                                      #STR109##                                   - 125 -- " " " "                                                                                                #STR110##                                   - 126 -- " " " "                                                                                                #STR111##                                   - 127 -- " " " "                                                                                                #STR112##                                   - 128 -- " " " "                                                                                                #STR113##                                   - 129 -- " " " "                                                                                                #STR114##                                   - 130 -- " " " "                                                                                                #STR115##                                   - 131 -- " " " "                                                                                                #STR116##                                   - 132 -- " " " "                                                                                                #STR117##                                   - 133 -- " " " "                                                                                                #STR118##                                   - 134 -- " " " "                                                                                                #STR119##                                   - 135 -- " " " "                                                                                                #STR120##                                   - 136 -- " " " "                                                                                                #STR121##                                   - 137 -- " " " "                                                                                                #STR122##                                   - 138 -- " " " "                                                                                                #STR123##                                   - 139 -- " " " "                                                                                                #STR124##                                   - 140 -- " " " "                                                                                                #STR125##                                   - 141 -- " " " "                                                                                                #STR126##                                   - 142 -- " " " "                                                                                                #STR127##                                   - 143 -- " " " "                                                                                               ##STR128##                                __________________________________________________________________________

                                      TABLE A-7                                   __________________________________________________________________________      #STR129##                                                                   Ex. No.                                                                           (R.sub.1)n                                                                       R.sub.2  X  R.sub.3      Y  R.sub.4                                    __________________________________________________________________________      144 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 NH                                                                  CH.sub.2                                                                      #STR131##                                   - 145 -- " " " "                                                                                                #STR132##                                   - 146 -- " "                                                                                                    " --OC.sub.2 H.sub.5                        - 147 -- " " " " --OH                                                         - 148 -- " " " "                                                                                                #STR134##                                   - 149 -- " " " "                                                                                                #STR135##                                   - 150 -- " " " "                                                                                                #STR136##                                   - 151 -- " " " "                                                                                                #STR137##                                   - 152 -- " " " "                                                                                                #STR138##                                   - 153 -- " " " "                                                                                                #STR139##                                   - 154 -- " " " "                                                                                                #STR140##                                   - 155 -- " " " " --NHC.sub.3 H.sub.7 -n                                       - 156 -- " " " "                                                                                                #STR141##                                   - 157 -- " " " "                                                                                                #STR142##                                   - 158 -- " " " "                                                                                                #STR143##                                   - 159 -- --CH.sub.2 CHO " " "                                                                                   #STR144##                                   - 160 -- --CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 " " " "                        - 161 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 "                                                                " TR145##                                                                     #STR146##                                   - 162 -- " " " "                                                                                                #STR147##                                   - 163 -- " " " "                                                                                               ##STR148##                                __________________________________________________________________________

                                      TABLE A-8                                   __________________________________________________________________________      #STR149##                                                                   Ex. No.                                                                           (R.sub.1)n                                                                       R.sub.2  X  R.sub.3      Y  R.sub.4                                    __________________________________________________________________________      164 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 NH                                                                  CH.sub.2                                                                      #STR151##                                   - 165 -- " CH.sub.2 " NH                                                                                        #STR152##                                   - 166 -- " " " "                                                                                                #STR153##                                   - 167 -- " " " "                                                                                                #STR154##                                   - 168 -- " NH                                                                                                   CH.sub.2                                                                      #STR156##                                   - 169 -- " "                                                                                                    " " 157##                                   - 170 -- " "                                                                                                    " TR158##                                                                     #STR159##                                   - 171 -- " "                                                                                                    " --O--(L-Menthyl)                          - 172 -- " " " " "                                                            - 173 -- " "                                                                                                    " --O--(D-Menthyl)                          - 174 -- " "                                                                                                    " TR162##                                                                     #STR163##                                   - 175 -- " " " " "                                                            - 176 -- " " " "                                                                                                #STR164##                                   - 177 -- " " " " --OCH.sub.2 CH.sub.2 Br                                     178 -- " " " " --OCH.sub.2 CH.sub.2 I                                          - 179 -- " " " "                                                                                                #STR165##                                   - 180 -- " " " "                                                                                                #STR166##                                   - 181 -- " " " "                                                                                                #STR167##                                   - 182 -- " " " "                                                                                                #STR168##                                   - 183 -- " " " "                                                                                               ##STR169##                                __________________________________________________________________________

                                      TABLE A-9                                   __________________________________________________________________________      #STR170##                                                                   Ex. No.                                                                           (R.sub.1)n                                                                       R.sub.2  X  R.sub.3      Y  R.sub.4                                    __________________________________________________________________________      184 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 NH                                                                  CH.sub.2                                                                      #STR172##                                   - 185 -- " "                                                                                                    " --O--(L-Menthyl)                          - 186 -- " " " " "                                                           187 -- " " " " --O--(D-Menthyl)                                                - 188 -- " " " "                                                                                                #STR174##                                   - 189 -- " " " " "                                                            - 190 -- " " " "                                                                                                #STR175##                                   - 191 -- " " " "                                                                                                #STR176##                                   - 192 -- " " " "                                                                                                #STR177##                                   - 193 -- " " " "                                                                                                #STR178##                                   - 194 -- " " " " "                                                            - 196 -- " "                                                                                                    " TR179##                                                                     #STR180##                                   - 197 -- " " " "                                                                                                #STR181##                                   - 198 -- --CH.sub.2 CHO " " "                                                                                   #STR182##                                   - 199 -- " " " " --OH                                                        200 -- " " " " --O--(L-Menthyl)                                                - 201 -- --CH.sub.2 CH═NOH " " "                                                                           ##STR183##                                __________________________________________________________________________

                                      TABLE B-1                                   __________________________________________________________________________      #STR184##                                                                   Ex. No.                                                                             (R.sub.2)n                                                                         R.sub.2      R.sub.3                                               __________________________________________________________________________      28 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2                                                           #STR185##                                              - 29 --                                                                                              " TR186##                                              - 30 --                                                                                              " TR187##                                              - 31 5-CH.sub.3 --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2 "                      32 5-Br " "                                                                    - 33 -- "                                                                                            #STR188##                                              - 34 -- "                                                                                            #STR189##                                              - 35 -- "                                                                                            #STR190##                                              - 36 -- "                                                                                            #STR191##                                              - 37 -- "                                                                                            #STR192##                                              - 38 -- "                                                                                            #STR193##                                              - 39 -- "                                                                                            #STR194##                                              - 40 -- " --C.sub.2 H.sub.5                                                __________________________________________________________________________

                  TABLE B-2                                                       ______________________________________                                          #STR195##                                                                     Ex.                                                                           No. (R.sub.2)n R.sub.2 R.sub.3                                              ______________________________________                                          41 -- --CH.sub.2 CH(OC.sub.2 H.sub.5).sub.2                                                             #STR196##                                            - 42 -- "                                                                                              #STR197##                                            - 43 5-F "                                                                                             #STR198##                                            - 44 5-OCH.sub.3 " "                                                          - 45 -- "                                                                                              #STR199##                                            - 46 -- "                                                                                              #STR200##                                            - 47 -- "                                                                                              #STR201##                                            - 48 -- "                                                                                              #STR202##                                            - 49 -- "                                                                                              #STR203##                                            - 50 -- "                                                                                              #STR204##                                            - 51 -- "                                                                                              #STR205##                                            - 52 -- "                                                                                              #STR206##                                            - 195  -- "                                                                                           ##STR207##                                         ______________________________________                                    

                  TABLE C                                                         ______________________________________                                                                 Gastric Acid                                            Gastric Receptor Secretion                                                    Binding Test Inhibition (%)                                                  Test Compound (Test Example 1) (Test Example 2)                               (Example No.) IC.sub.50 (nM) 10 mg/kg, i.d.                                 ______________________________________                                        10           2.5         59                                                     14 2.2 49                                                                     71 1.1 48                                                                     79 1.9 47                                                                     81 1.6 59                                                                     82 6.2 56                                                                     84 3.4 68                                                                     85 1.2 72                                                                     89 5.8 65                                                                     92 4.3 57                                                                     94 3.5 70                                                                     111 5.1 69                                                                    114 2.4 56                                                                    122 2.9 62                                                                    124 5.3 54                                                                    125 2.5 54                                                                    129 3.6 71                                                                    130 4.9 71                                                                    131 23 65                                                                     132 8.9 52                                                                    138 2.2 69                                                                    143 1.5 64                                                                    148 1.1 63                                                                    149 0.93 69                                                                   151 2.9 62                                                                    152 2.1 64                                                                    154 1.0 59                                                                    156 6.5 69                                                                    158 1.4 66                                                                    168 2.6 61                                                                    169 1.9 52                                                                    170 5.1 63                                                                    174 0.54 70                                                                   179 1.6 63                                                                    180 4.6 73                                                                    181 2.2 69                                                                    188 0.35 76 (3 mg/kg)                                                         190 0.68 70                                                                   191 5.5 78                                                                  ______________________________________                                    

                  TABLE D                                                         ______________________________________                                        Compound                                                                              CCK-B Receptor                                                                              Compound  CCK-B Receptor                                  No. Binding Test No. Binding Test                                             (Example (Test Example 3) (Example (Test Example 3)                           No.) IC.sub.50 (nM) No.) IC.sub.50 (nM)                                     ______________________________________                                        62      1.2           129       0.39                                            65 0.76 130 2.3                                                               66 0.76 180 0.36                                                              71 1.2 92 0.90                                                                174 0.42 143 1.9                                                              7 0.07 181 0.78                                                               111 0.35 156 2.8                                                              114 0.64 191 0.45                                                             138 0.50 158 0.56                                                             179 0.14 190 0.10                                                             122 0.18                                                                    ______________________________________                                    

Industrial Applicability

The compounds according to the present invention exhibit selectiveantagonism against gastrin receptors without causing side effectsattributed to CCK-A receptor antagonism and are useful for the treatmentand prevention of diseases of digestive organs, such as peptic ulcers,gastritis, reflux esophagitis, and Zollinger-Ellison syndrome. Thecompounds are also useful for the treatment of tumours originating inthe gastrointestinal system and which also antagonizes selectivelyagainst CCK-B receptors and are useful for the treatment of CCK-relateddisorders in the appetite control system, enhancement and prolongationof analgesia through opiate or non-opiate, induction of anesthesia oranalgesia, and the treatment and prevention of symptoms of psychoticdisorders, including anxiety and panic disorders.

What is claimed is:
 1. A compound represented by formula (II):##STR208## wherein R₁ represents a halogen atom; a lower alkyl group; alower alkoxy group; a hydroxyl group; a nitro group; a trifluoromethylgroup; a lower alkylthio group; a carbonyl group which is substituted bya hydrogen atom, a lower alkyl group, a carbocylic aryl group having6-14 carbon atoms, lower alkoxy group or an amino group; a carboxylgroup; a mercapto group; or a substituted or unsubstituted aminogroup;R₃ represents a substituted or unsubstituted pyridyl group; nrepresents an integer of from 0 to 4; and R₉ represents a grouprepresented by formula (III): ##STR209## wherein R₁₀ and R₁₁ eachrepresent a substituted or unsubstituted lower alkyl group having 1-6carbon atoms, or a group represented by formula (IV): ##STR210## whereinZ represents a substituted or unsubstituted lower alkylene group having1-8 carbon atoms, or a salt thereof or an optically active isomerthereof wherein the substituents in the definition of R1, R3, R10, R11and Z represent a halogen atom; a lower alkyl group having 1-6 carbonatoms; a C3-C8 cycloalkyl group; a C6-C14 aryl group; a hydroxyl group;a lower alkoxy group having 1-6 carbon atoms; a C6-C14 aryloxy group; alower alkylthio group; 'CH(OR')₂, wherein R' represents a lower alkylgroup having 1-6 carbon atoms; a lower alkylcarbonyl group; a C6-C14arylcarbonyl group; a carboxyl group; a lower alkoxycarbonyl group; anamino group which may be substituted with one to two methyl groups, anethyl group or a trifluoromethylcarbonyl group; an imino group;--CR"(SR')₂, wherein R' and R" represent a lower alkyl group having 1-6carbon atoms; a nitro group; a nitrile group; or a trifluoromethylgroup.